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FKBP12 Assay FKBP12 assay using rapamycin analogs. ChEMBL_305479 (CHEMBL830270) Inhibition of Mammalian target of Rapamycin mTOR ChEMBL_2430724 Inhibition of hypoxia induced VEGFR-2 (unknown origin) ChEMBL_750098 (CHEMBL1787515) Inhibition of hypoxia-induced HIF1alpha transcriptional activity in HEK293 cells incubated for 16 hrs by hypoxia response element-driven luciferase reporter gene assay ChEMBL_481746 (CHEMBL1002847) Inhibition of hypoxia-induced HIF1 activation in human U251 cells ChEMBL_1989567 (CHEMBL4623302) Inhibition of Vps34 in human MCF7-LC3 cells assessed as rapamycin-induced autophagy ChEMBL_321108 (CHEMBL882874) Effective concentration to inhibit production of hypoxia inducible factor 1-alpha protein ChEMBL_475987 (CHEMBL931441) Inhibition of hypoxia-induced HIF1 activation in human AGS cells by reporter gene assay ChEMBL_527926 (CHEMBL975114) Inhibition of hypoxia-induced HIF1 activation in human T47D cells by reporter gene assay ChEMBL_527928 (CHEMBL975116) Inhibition of hypoxia-induced HIF1 activation in human PC3 cells by reporter gene assay ChEMBL_767399 (CHEMBL1825511) Inhibition of hypoxia-induced HIF1 activation in human LN229 cells expressing HRE-AP reporter gene preincubated for 1 hr under normoxia condition followed by 24 hrs incubation under hypoxia condition by HRE-luciferase reporter assay ChEMBL_1294789 (CHEMBL3128876) Inhibition of Stat3 phosphorylation in human OVCAR3 cells by Western blotting analysis in hypoxia condition ChEMBL_1294791 (CHEMBL3128878) Inhibition of Stat3 phosphorylation in human PANC1 cells by Western blotting analysis in hypoxia condition ChEMBL_550371 (CHEMBL999925) Inhibition of hypoxia-induced HIF1 activation in human HeLa cells by luciferase reporter gene assay ChEMBL_1294796 (CHEMBL3128919) Inhibition of HIF-1 alpha in human OVCAR3 cells by Western blotting analysis in hypoxia condition ChEMBL_1294797 (CHEMBL3128920) Inhibition of HIF-1 alpha in human PANC1 cells by Western blotting analysis in hypoxia condition ChEMBL_458038 (CHEMBL924307) Inhibition of hypoxia induced HIF1-alpha transcriptional activity in human Hep3B cells by reporter gene assay ChEMBL_458039 (CHEMBL924308) Inhibition of hypoxia induced HIF1-alpha transcriptional activity in human AGS cells by reporter gene assay ChEMBL_469602 (CHEMBL933161) Inhibition of hypoxia-induced HIF1 transcriptional activation in human U251-HRE cells by luciferase reporter assay ChEMBL_478428 (CHEMBL932617) Inhibition of hypoxia-induced HIF1 activation in human T47D cells by cell based reporter gene assay ChEMBL_1294792 (CHEMBL3128879) Inhibition of Stat3 phosphorylation in human MDA-MB-468 cells by Western blotting analysis in hypoxia condition ChEMBL_1294793 (CHEMBL3128880) Inhibition of Stat3 phosphorylation in human MDA-MB-231 cells by Western blotting analysis in hypoxia condition ChEMBL_2281079 Inhibition of hypoxia-induced HIF1alpha/P300 interaction (unknown origin) incubated for 30 mins for fluorescence anisotropy competition assay ChEMBL_428795 (CHEMBL916228) Inhibition of hypoxia induced HIF1 transcriptional activity in human Hep3B cells by cell-based HRE reporter assay ChEMBL_458037 (CHEMBL924306) Inhibition of hypoxia induced HIF1-alpha transcriptional activity in human Sk-Hep1 cells by reporter gene assay ChEMBL_573857 (CHEMBL1056199) Inhibition of hypoxia-induced HIF1 activation in human Hep3B cells by pGL3-HRE-luciferase reporter gene assay ChEMBL_619005 (CHEMBL1101830) Inhibition of hypoxia-induced HIF1 activation in human T47D cells by pTK-HRE3-luciferase reporter gene assay ChEMBL_698465 (CHEMBL1647397) Inhibition of hypoxia-induced HIF1 activation in human T47D cells by HRE3-TK-luciferase reporter gene assay ChEMBL_698468 (CHEMBL1647400) Inhibition of hypoxia-induced HIF1 activation in human PC3 cells by HRE3-TK-luciferase reporter gene assay ChEMBL_770820 (CHEMBL1837625) Inhibition of hypoxia-induced HIF1alpha activation in human ME180 cells by HRE3-Bla-luciferase reporter gene assay ChEMBL_881925 (CHEMBL2212528) Inhibition of HIF-1alpha in human HCT116 cells under hypoxia condition by HRE-luciferase reporter gene assay ChEMBL_881926 (CHEMBL2212529) Inhibition of HIF-1alpha in human LN229 cells under hypoxia condition by HRE-luciferase reporter gene assay ChEMBL_1294798 (CHEMBL3128921) Inhibition of HIF-1 alpha in human MDA-MB-468 cells by Western blotting analysis in hypoxia condition ChEMBL_1294799 (CHEMBL3128922) Inhibition of HIF-1 alpha in human MDA-MB-231 cells by Western blotting analysis in hypoxia condition ChEMBL_452324 (CHEMBL901549) Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by cell based luciferase assay ChEMBL_550357 (CHEMBL999911) Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by luciferase reporter gene assay ChEMBL_753564 (CHEMBL1799182) Inhibition of hypoxia-induced HIF1alpha activation in human Hep3B cells after 16 hrs by HRE-luciferase reporter assay ChEBML_1685544 Inhibition of hypoxia-induced HIF1alpha (unknown origin) transcriptional activity expressed in human HCT116 cells by HRE luciferase reporter gene assay ChEMBL_610892 (CHEMBL1065047) Inhibition of hypoxia-induced HIF1alpha activation in human HeLa cells after 12 hrs by HRE-luciferase reporter gene assay ChEMBL_1627457 (CHEMBL3869978) Inhibition of hypoxia-induced HIF1 transcriptional activity in human HeLa cells measured after 12 hrs by luciferase reporter gene assay ChEMBL_481732 (CHEMBL1002833) Inhibition of hypoxia-induced HIF1 activation in human T47D cells carrying pTK-HER3-luc reporter gene measured by luciferase activity ChEMBL_526045 (CHEMBL967263) Inhibition of hypoxia-induced HIF1 activation in human AGS cells after 16 hrs by pGL3-HRE-luciferase reporter gene assay ChEMBL_549581 (CHEMBL1015932) Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by pTK-HRE3-luciferase reporter gene assay ChEMBL_621709 (CHEMBL1104951) Inhibition of hypoxia-induced HIF1 activation in human PC3 cells after 16 hrs by pTK-HRE3-luciferase reporter gene assay ChEMBL_621727 (CHEMBL1108459) Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by pTK-HRE3-luciferase reporter gene assay ChEMBL_621731 (CHEMBL1108463) Inhibition of hypoxia-induced HIF1 activation in human T47D cells expressing pGL3 construct after 16 hrs by reporter gene assay ChEMBL_776653 (CHEMBL1913750) Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by HRE3-TK-luciferase reporter gene assay ChEMBL_851302 (CHEMBL2155888) Inhibition of hypoxia-induced HIF1 activation in human T47D cells after 16 hrs by HRE3-TK-luciferase reporter gene assay ChEMBL_2288784 Inhibition of DHODH in human HeLa cells assessed as reduction in hypoxia-induced VEGF expression incubated for 48 hrs by ELISA assay ChEMBL_631037 (CHEMBL1113762) Inhibition of hypoxia-induced HIF1 activation in human T47D cells in presence of 1% O2 by HRE3-TK-luc reporter assay ChEMBL_2375999 Inhibition of HIF-1 alpha transcriptional activity in human U-251 cells incubated for 24 hrs under hypoxia condition by luciferse reporter assay ChEMBL_439940 (CHEMBL890257) Inhibition of HIF1 activation in human AGS cells assessed as inhibition of hypoxia-induced luciferase expression after 16 hrs by reporter assay ChEMBL_439941 (CHEMBL890258) Inhibition of HIF1 activation in human Hep3B cells assessed as inhibition of hypoxia-induced luciferase expression after 16 hrs by reporter assay ChEMBL_735620 (CHEMBL1693322) Inhibition of hypoxia-induced HIF1 activation in human T47D cells expressing pGL3 construct after 16 hrs by cell-based luciferase reporter assay ChEMBL_938618 (CHEMBL2327238) Inhibition of hypoxia-induced HIF1alpha transcriptional activity in human HeLa cells expressing HRE-Luc after 12 hrs by luciferase reporter gene assay Evaluation of Inhibitory Activity Against Retinal Neovascularization by Hypoxia The experiment was performed in order to evaluate inhibitory activity against angiogenesis of the compounds. ChEMBL_573855 (CHEMBL1055397) Inhibition of hypoxia-induced HIF1alpha protein accumulation in human Hep3B cells treated for 30 mins measured after 12 hrs by Western blot analysis ChEMBL_631036 (CHEMBL1113761) Inhibition of chemical hypoxia-induced HIF1 activation in human T47D cells in presence of 1, 10-phenanthrolin by HRE3-TK-luc reporter assay ChEMBL_636313 (CHEMBL1169036) Inhibition of hypoxia-induced HIF1alpha protein accumulation in human Hep3B cells treated for 30 mins measured after 12 hrs by Western blot analysis ChEMBL_1855371 (CHEMBL4356100) Inhibition of HIF1alpha transcriptional activity in hypoxia-induced human HCCLM3 cells co-transfected with luciferase reporter plasmid containing five copies of HREs and pRL-SV40 plasmid encoding Renilla luciferase incubated with compound under normoxia for 1 hr followed by hypoxia induction and measured after 24 hrs by HRE-dependent dual luciferase reporter gene assay ChEBML_66293 The compound was tested for binding affinity to FK506 binding protein 12 using Rapamycin as control, with an ascomycin conjugate of alkaline phosphatase in a competition binding assay ChEMBL_1891621 (CHEMBL4393448) Inhibition of hypoxia-induced HIF1alpha transcriptional activity in human Hep3B cells after 24 hrs in hypoxic condition by HRE-dependent dual luciferase reporter gene assay ChEMBL_66293 (CHEMBL678815) The compound was tested for binding affinity to FK506 binding protein 12 using Rapamycin as control, with an ascomycin conjugate of alkaline phosphatase in a competition binding assay ChEMBL_1766949 (CHEMBL4202196) Inhibition of HIF-1alpha in human HRE-A549 cells pre-incubated for 1 hr before exposure to hypoxia for 24 hrs by HRE-luciferase reporter gene assay ChEMBL_881913 (CHEMBL2212516) Inhibition of topoisomerase-1 in human U251 cells assessed as inhibition of HIF-1-mediated hypoxia-induced VEGF expression after 24 hrs by luciferase reporter gene assay ChEMBL_881914 (CHEMBL2212517) Inhibition of topoisomerase-1 in human U251 cells assessed as inhibition of hypoxia-induced HIF-1alpha accumulation in nuclear extract after 6 to 24 hrs by immunoblot analysis ChEMBL_2080981 (CHEMBL4736772) Binding affinity to FKBP12 (unknown origin) expressed in HEK293 cells co-expressing FRB assessed as inhibition of rapamycin-induced FKBP12-FRB dimerization measured after 25 mins by nano-glo live cell reagent based luminescence assay ChEMBL_1465276 (CHEMBL3406495) Inhibition of HIF1 in human HT1080 cells transfected with 5xHRE/pGL3/VEGF/E1b reporter plasmid pre-incubated for 1 hr followed by incubation under hypoxia conditions for 24 hrs by HRE-driven luciferase reporter gene assay ChEMBL_860195 (CHEMBL2168935) Inhibition of P300 CH1 domain-mediated HIF1 transcriptional activity in human LN229-V6R cells assessed as reduction in luciferase activity incubated for 1 hr under normoxia followed by 24 hrs under hypoxia by reporter gene assay ChEMBL_829292 (CHEMBL2060139) Inhibition of HIF1 transcriptional activity in human LN229 cells expressing VEGF-HRE-V6R and coexpressing luciferase, lac Z gene incubated for 1 hr in normoxia condition followed by 24 hrs in hypoxia condition by reporter gene assay ChEMBL_2050089 (CHEMBL4704788) Inhibition of hypoxia-induced HIF1alpha transcriptional activity in human Hep3B cells co-transfected with luciferase reporter plasmid containing six copies of HREs and pRL-CMV vector assessed as reduction in luciferase activity incubated for 24 hrs under hypoxic condition by HRE-dependent dual luciferase reporter gene assay ChEMBL_2102766 (CHEMBL4811162) Inhibition of hypoxia-induced HIF1 alpha transcriptional activity in human HeLa cells transfected with luciferase reporter containing of HRE assessed as reduction in luciferase activity incubated for 1 hrs under normoxic condition followed by incubation under hypoxic condition for 24 hrs by luciferase reporter gene assay ChEMBL_2128544 (CHEMBL4837973) Inhibition of hypoxia-induced HIF1alpha transcriptional activity in human Hep3B cells co-transfected with luciferase reporter plasmid containing six copies of HREs and pRL-CMV vector assessed as reduction in luciferase activity incubated for 24 hrs under hypoxic condition by HRE-dependent dual luciferase reporter gene assay Confirmatory Cherry Pick 3 SAR Dose Response Multiplex in TOR pathway GFP-fusion proteins for Saccharomyes cerevisiae, specifically AGP1 University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae Assay Provider: Maggie Werner-Washburne, UNM Screening Center/ PI: UNMCMD/ Larry Sklar Lead Biologist: Jun Chen Chemistry Center/ PI: University of Kansas Specialized Chemistry Center/ Jeff Aube Chemistry Center Lead: Jennifer Golden, Blake Peterson Assay Implementation: Jun Chen, Stephanie Sedillo, Anna Waller, Annette Evangelisti, Cristian Bologa, Oleg Ursu, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although t Confirmatory Cherry Pick 3 SAR Dose Response Multiplex in TOR pathway GFP-fusion proteins for Saccharomyes cerevisiae, specifically CIT2 University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae Assay Provider: Maggie Werner-Washburne, UNM Screening Center/ PI: UNMCMD/ Larry Sklar Lead Biologist: Jun Chen Chemistry Center/ PI: University of Kansas Specialized Chemistry Center/ Jeff Aube Chemistry Center Lead: Jennifer Golden, Blake Peterson Assay Implementation: Jun Chen, Stephanie Sedillo, Anna Waller, Annette Evangelisti, Cristian Bologa, Oleg Ursu, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although th Confirmatory Cherry Pick 3 SAR Dose Response Multiplex in TOR pathway GFP-fusion proteins for Saccharomyes cerevisiae, specifically LAP4 University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae Assay Provider: Maggie Werner-Washburne, UNM Screening Center/ PI: UNMCMD/ Larry Sklar Lead Biologist: Jun Chen Chemistry Center/ PI: University of Kansas Specialized Chemistry Center/ Jeff Aube Chemistry Center Lead: Jennifer Golden, Blake Peterson Assay Implementation: Jun Chen, Stephanie Sedillo, Anna Waller, Annette Evangelisti, Cristian Bologa, Oleg Ursu, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although t Confirmatory Cherry Pick 3 SAR Dose Response Multiplex in TOR pathway GFP-fusion proteins for Saccharomyes cerevisiae, specifically MEP2 University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae Assay Provider: Maggie Werner-Washburne, UNM Screening Center/ PI: UNMCMD/ Larry Sklar Lead Biologist: Jun Chen Chemistry Center/ PI: University of Kansas Specialized Chemistry Center/ Jeff Aube Chemistry Center Lead: Jennifer Golden, Blake Peterson Assay Implementation: Jun Chen, Stephanie Sedillo, Anna Waller, Annette Evangelisti, Cristian Bologa, Oleg Ursu, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although t Confirmatory Cherry Pick 3 SAR Dose Response Multiplex in TOR pathway GFP-fusion proteins for Saccharomyes cerevisiae, specifically RPL19A University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae Assay Provider: Maggie Werner-Washburne, UNM Screening Center/ PI: UNMCMD/ Larry Sklar Lead Biologist: Jun Chen Chemistry Center/ PI: University of Kansas Specialized Chemistry Center/ Jeff Aube Chemistry Center Lead: Jennifer Golden, Blake Peterson Assay Implementation: Jun Chen, Stephanie Sedillo, Anna Waller, Annette Evangelisti, Cristian Bologa, Oleg Ursu, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although t mTOR Assay Mammalian target of rapamycin (mTOR) was assayed by monitoring phosphorylation of GFP-4EBP using a homogeneous time-resolved fluorescence resonance energy transfer format. The mTOR-mediated phosphorylation was measured under initial rate conditions. After incubation, the phosphorylated substrate was detected with Tb-anti-p4E-BP1 antibody before reading on a Perkin-Elmer EnVision Fluorescence Reader (exc 340; em 495/520). Duplicate dose-response curves were fit to an equation of competitive tight-binding inhibition. Dose Response of TOR pathway GFP-fusion proteins in Saccharomyes cerevisiae specifically AGP1 based on MLPCN hits University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae PI: Maggie Werner-Washburn Center PI: Larry Sklar Assay Implementation: Jun Chen, Chris Allen, Susan Young, Anna Waller, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although the signaling events up- and downstream of TORC2 (which regulates spatial aspects of growth) have yet to be elucidated in detail, it is well established that TORC1 is a central hub of a signaling network that couples cues from hormones and growth Dose Response of TOR pathway GFP-fusion proteins in Saccharomyes cerevisiae specifically CIT2 based on MLPCN hits University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae PI: Maggie Werner-Washburn Center PI: Larry Sklar Assay Implementation: Jun Chen, Chris Allen, Susan Young, Anna Waller, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although the signaling events up- and downstream of TORC2 (which regulates spatial aspects of growth) have yet to be elucidated in detail, it is well established that TORC1 is a central hub of a signaling network that couples cues from hormones and growth Dose Response of TOR pathway GFP-fusion proteins in Saccharomyes cerevisiae specifically LAP4 based on MLPCN hits University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae PI: Maggie Werner-Washburn Center PI: Larry Sklar Assay Implementation: Jun Chen, Chris Allen, Susan Young, Anna Waller, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although the signaling events up- and downstream of TORC2 (which regulates spatial aspects of growth) have yet to be elucidated in detail, it is well established that TORC1 is a central hub of a signaling network that couples cues from hormones and growth Dose Response of TOR pathway GFP-fusion proteins in Saccharomyes cerevisiae specifically MEP2 based on MLPCN hits University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae PI: Maggie Werner-Washburn Center PI: Larry Sklar Assay Implementation: Jun Chen, Chris Allen, Susan Young, Anna Waller, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although the signaling events up- and downstream of TORC2 (which regulates spatial aspects of growth) have yet to be elucidated in detail, it is well established that TORC1 is a central hub of a signaling network that couples cues from hormones and growth Dose Response of TOR pathway GFP-fusion proteins in Saccharomyes cerevisiae specifically RPL19A based on MLPCN hits University of New Mexico Assay Overview: Assay Support: 1R03 MH086450-01 Project Title: Chemical Screen of TOR pathway GFP fusion proteins in S. cerevisiae PI: Maggie Werner-Washburn Center PI: Larry Sklar Assay Implementation: Jun Chen, Chris Allen, Susan Young, Anna Waller, Mark Carter Assay Background and Significance: The target of rapamycin, TOR, is a ser/thr protein kinase evolutionarily conserved from yeast to man [Wullschleger, et al. 2006]. TOR functions in two distinct protein complexes, TOR complex 1 (TORC1) and TORC2 [Cafferkey, et al. 1993; Stan, et al. 1994]. Curiously, only TOR in TORC1 is bound and inhibited by the lipophilic macrolide rapamycin [Kunz, et al. 1993; Helliwell, et al. 1998; Zhang, et al. 2006]. Although the signaling events up- and downstream of TORC2 (which regulates spatial aspects of growth) have yet to be elucidated in detail, it is well established that TORC1 is a central hub of a signaling network that couples cues from hormones and growth In Vitro Inhibition Assay The Invitrogen (Carlsbad, Calif.) mammalian target of rapamycin (mTOR) Lanthascreen assay can be used to quantitate mTOR kinase activity in an in vitro setting. Active mTOR phosphorylates eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) on residue threonine 46. This phosphorylation event can be detected with a phospho-specific terbium (Tb) labeled Ab, in turn bringing the Tb label in close proximity to the GFP tagged 4E-BP1 and allowing for time-resolved fluorescence resonance energy transfer (TR-FRET), which correlates 4E-BP1 phosphorylation levels with mTOR kinase activity. In Vitro mTOR Assay The Invitrogen (Carlsbad, Calif.) mammalian target of rapamycin (mTOR) Lanthascreen assay can be used to quantitate mTOR kinase activity in an in vitro setting. Active mTOR phosphorylates eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) on residue threonine 46. This phosphorylation event can be detected with a phospho-specific terbium (Tb) labeled Ab, in turn bringing the Tb label in close proximity to the GFP tagged 4E-BP 1 and allowing for time-resolved fluorescence resonance energy transfer (TR-FRET), which correlates 4E-BP1 phosphorylation levels with mTOR kinase activity. SAR analysis for the identification of translation initiation inhibitors (PABP) Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG) Source Affiliation: Sanford-Burnham Medical Research Institute(SBMRI, San Diego, CA) Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN) Grant Number: 1R03MH084835-01 Assay Provider: Jerry Pelletier, Ph.D, McGill University, Montreal, Canada Translation is an essential cellular process whose deregulation is associated with alterations in cell growth, cell cycle progression, and cell death responses. The initiation phase of translation is a key target for regulation when cells are exposed to various environmental cues (e.g. insulin, amino acid starvation, mitogenic stimulation, hypoxia, etc). As well, translation initiation control is usurped upon viral infection and is deregulated in many human cancers. Over-expression of certain translation factors can lead to malignant transformation and many of the components of the translational apparatus are over-expressed in human cancers. Several tumor sup SAR analysis for the identification of translation initiation inhibitors (eIF4H) Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG) Source Affiliation: Sanford-Burnham Medical Research Institute (SBIMR, San Diego, CA) Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN) Grant Number: 1R03MH084835-01 Assay Provider: Jerry Pelletier, Ph.D, McGill University, Montreal, Canada Translation is an essential cellular process whose deregulation is associated with alterations in cell growth, cell cycle progression, and cell death responses. The initiation phase of translation is a key target for regulation when cells are exposed to various environmental cues (e.g. insulin, amino acid starvation, mitogenic stimulation, hypoxia, etc). As well, translation initiation control is usurped upon viral infection and is deregulated in many human cancers. Over-expression of certain translation factors can lead to malignant transformation and many of the components of the translational apparatus are over-expressed in human cancers. Several tumor su uHTS fluorescence polarization assay for the identification of translation initiation inhibitors (PABP) Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG) Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA) Network: NIH Molecular Libraries Production Centers Network (MLPCN) Grant Number: 1R03MH084835-01 Assay Provider: Jerry Pelletier, Ph.D, McGill University, Montreal, Canada Translation is an essential cellular process whose deregulation is associated with alterations in cell growth, cell cycle progression, and cell death responses. The initiation phase of translation is a key target for regulation when cells are exposed to various environmental cues (e.g. insulin, amino acid starvation, mitogenic stimulation, hypoxia, etc). As well, translation initiation control is usurped upon viral infection and is deregulated in many human cancers. Over-expression of certain translation factors can lead to malignant transformation and many of the components of the translational apparatus are over-expressed in human cancers. Several tumor suppresso uHTS fluorescence polarization assay for the identification of translation initiation inhibitors (eIF4H) Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG) Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA) Network: NIH Molecular Libraries Production Centers Network (MLPCN) Grant Number: 1R03MH084835-01 Assay Provider: Jerry Pelletier, Ph.D, McGill University, Montreal, Canada Translation is an essential cellular process whose deregulation is associated with alterations in cell growth, cell cycle progression, and cell death responses. The initiation phase of translation is a key target for regulation when cells are exposed to various environmental cues (e.g. insulin, amino acid starvation, mitogenic stimulation, hypoxia, etc). As well, translation initiation control is usurped upon viral infection and is deregulated in many human cancers. Over-expression of certain translation factors can lead to malignant transformation and many of the components of the translational apparatus are over-expressed in human cancers. Several tumor suppresso PI3K Inhibition Assay PI3K inhibition assay (PI3K Assay (Emmanuelle M, Huang Y, Yan H G et al. Targeting Protein Translation in Human Non-Small Cell Lung Cancer via Combined MEK and Mammalian Target of Rapamycin Suppression. Cancer Res 67:(23). (2007).) was carried out by PI3 Kinase activity/inhibitor assay kit, where PI3 kinase reaction was set up in Glutathione-coated strips/plate for inhibitor reaction. Kinase and inhibitors were pre-incubated for 10 minutes prior to the addition of PIP2 substrate. 5 uL of 5x kinase reaction buffer were added in each well followed by the further addition of 5 uL/well of PIP2 substrate. Then distilled H2O was added to each well so as to make up a final volume of 25 uL/well. Incubation was done at rt for 1 hour which was followed by washing the wells 3 times with 200 uL of 1xTBST per well and then 2 times with 200 uL of IX TBS per well. Then 100 uL of the Substrate TMB per well was added and then to keep for colour development in the dark. SPR Assay to Determine Binding Affinity to FKBP51 Biotinylated avi-FKBP51 was immobilized on a streptavidin chip (Cytiva Series S SA) using a Biacore 8K or 8 k+ (Cytiva). To achieve an immobilization level of 2000 RU, 3 μg/ml biotinylated avi-FKBP51 were injected for 360 sec at a flow rate of 10 μl/min. Rapalogs were diluted in DMSO to 100× working concentration. Each Rapalog was 100-fold diluted in 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20 and a serial dilution prepared (8 concentrations, 3-fold dilutions, 0.5-1000 nM). Rapamycin was used as reference sample (8 concentrations, 3-fold dilutions, 0.5-1000 nM). The compound dilutions were then injected at 100 uL/min for 120 seconds contact time and with 3600 seconds dissociation time with increasing concentrations. 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, 1% DMSO was used as running buffer. Multi-cycle kinetics data were fit to a 1:1 binding model to measure the association rate ka (1/Ms), the dissociation rate kd (1/s) and the affinity Kd (M). SPR Assay to Determine Binding Affinity to FKBP12 Biotinylated avi-FKBP12 was immobilized on a streptavidin chip (Cytiva Series S SA) using a Biacore 8K or 8 k+ (Cytiva). To achieve an immobilization level of 1000 RU, 2 μg/ml biotinylated avi-FKBP12 were injected for 100 sec at a flow rate of 10 μl/min. Rapalogs were diluted in DMSO to 100× working concentration. Each Rapalog was 100-fold diluted in 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20 and a serial dilution prepared (9 concentrations, 3-fold dilutions, 0.08-500 nM). Rapamycin was used as reference sample (9 concentrations, 3-fold dilutions, 0.02-100 nM). The compound dilutions were then injected at 100 uL/min for 120 seconds contact time in sequence with increasing concentrations. Dissociation was monitored for 3600 seconds. 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, 1% DMSO was used as running buffer. The single-cycle kinetics data were fit to a 1:1 binding model to measure the association rate ka (1/Ms), the dissociation rate kd (1/s) and the affinity Kd (M). SPR Assay to Characterize Ternary Complex Formation with FKBP12 Biotinylated avi-FKBP12 was immobilized on a streptavidin chip (Cytiva Series S SA) using a Biacore 8K or 8 k+ (Cytiva). To achieve an immobilization level of 100 RU, 0.3 g/ml biotinylated avi-FKBP12 were injected for 80 sec at a flow rate of 10 l/min. Serial dilution of FRB was prepared (12 concentrations, 3-fold dilutions, 0.00011-20 M) and supplemented with 100 nM of rapalog. A-B-A injection mode was used to ensure saturation immobilized FKBP12 with respective rapalog. 100 nM solution of the respective rapalog was injected before FRB injection for 120 sec and during dissociation for 420 sec. The FRB dilutions were then injected 120 seconds contact time with increasing concentrations. Rapamycin was used as reference sample. 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, 1% DMSO was used as running buffer at a flow rate of 30 l/min. The multi-cycle kinetics data were fit to a 1:1 binding model to measure the association rate ka (1/Ms), the dissociation rate kd (1/s) and the affinity Kd (M). In case of fast association and dissociation, steady state affinity analysis following the law of mass action was used to determine the affinity Kd (M). SPR Assay to Characterize Ternary Complex Formation with FKBP51 Biotinylated avi-FKBP51 was immobilized on a streptavidin chip (Cytiva Series S SA) using a Biacore 8K or 8 k+ (Cytiva). To achieve an immobilization level of 200 RU, 0.6 g/ml biotinylated avi-FKBP51 were injected for 150 sec at a flow rate of 10 l/min. Serial dilution of FRB was prepared (12 concentrations, 3-fold dilutions, 0.00011-20 M) and supplemented with 100 nM of rapalog. A-B-A injection mode was used to ensure saturation immobilized FKBP12 with respective rapalog. 100 nM solution of the respective rapalog was injected before FRB injection for 120 sec and during dissociation for 420 sec. The FRB dilutions were then injected 120 seconds contact time with increasing concentrations. Rapamycin was used as reference sample. 50 mM HEPES pH 7.5, 150 mM NaCl, 2 mM MgCl2, 1 mM DTT, 0.05% Tween-20, 1% DMSO was used as running buffer at a flow rate of 30 l/min. The multi-cycle kinetics data were fit to a 1:1 binding model to measure the association rate ka (1/Ms), the dissociation rate kd (1/s) and the affinity Kd (M). In case of fast association and dissociation, steady state affinity analysis following the law of mass action was used to determine the affinity Kd (M). Inhibitory Effect of the Compounds on PHD2 The interaction between hypoxia-inducible factor HIF-1α and VBC complex (von Hippel-Lindau protein-Elongin B-Elongin C, VBC) was detected by Fluorescence polarization (FP) method, to measure the enzyme inhibitory activity of the HIF Prolyl hydroxylases 2 (PHD2) inhibitor compounds.To a NETN (20 mM Tris.HCl, 100 mM NaCl, 1 mM EDTA, 0.5% NP-40, 1 mM PMSF) buffer containing 200 μM ascorbic acid, 20 μM α-ketoglutaric acid, 100 μM FeCl2 was added FAM-HIF (556-575) at a final concentration of 1 μM in the dark. Subsequently, the desired concentration of the test compound or the positive compound was added (the compound was replaced by the buffer in the negative control and the positive control). Finally, PHD2 was added at a final concentration of 0.5 μg/μl (PHD2 was replaced by the buffer in the negative control). They were mixed well and allowed to stand at room temperature for 30 minutes in the dark followed by 95° C. water bath for 1 minute, and then the reaction was terminated. After the temperature drops to room temperature, the sample was prepared well for use. EBC buffer (50 mM Tris.HCl, 120 mM NaCl, 0.5% NP-40) was added to the corresponding wells of a black 96-well test plate. A GST-VBC complex was added to the corresponding test wells at a final concentration of 300 nM (using the wells containing only EBC buffer as blank wells). Subsequently, the corresponding PHD2 prolyl hydroxylation reaction sample was added in the dark as a substrate with a final concentration of 100 nM. After mixing well, the lateral and longitudinal fluorescence intensity values were measured using a full-wavelength multifunctional microplate reader (TECAN infinite M1000) at an excitation wavelength of 407 nm and an emission wavelength of 518 nm.
BDBM92863 mTOR Inhibitor, Rapamycin US9505773, Rapamycin
CHEMBL437064 Rapamycin analogue BDBM50089437
Rapamycin analogue CHEMBL281297 BDBM50089447
BDBM36608 Rapamycin C-7, analog 1
BDBM36610 Rapamycin C-7, analog 5a
BDBM36612 Rapamycin C-7, analog 6a
BDBM36613 Rapamycin C-7, analog 6b
BDBM36614 Rapamycin C-7, analog 7a
BDBM36615 Rapamycin C-7, analog 7b
BDBM36616 Rapamycin C-7, analog 8a
BDBM36617 Rapamycin C-7, analog 8b
BDBM36618 Rapamycin C-7, analog 9
BDBM36619 Rapamycin C-7, analog 10a
BDBM36621 Rapamycin C-7, analog 11a
BDBM36622 Rapamycin C-7, analog 11b
BDBM36625 Rapamycin C-7, analog 14a
BDBM36626 Rapamycin C-7, analog 15a
BDBM36627 Rapamycin C-7, analog 16a
BDBM36628 Rapamycin C-7, analog 17a
Rapamycin C-7, analog 10b BDBM36620
Rapamycin C-7, analog 12 BDBM36623
Rapamycin C-7, analog 13 BDBM36624
Rapamycin C-7, analog 5b BDBM36611
Rapamycin C-7, analog 4 BDBM36609 US11603377, Compound Ramycin SIROLIMUS
BDBM757304 (S)-C16-(1,1-dioxidoisothiazolidin-2-yl)-C32-deoxo-rapamycin US20250223297, Example 1
Sirolimus BDBM50064359 1,18-Dihydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-ethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.0*4,9*]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone (Rapamycin) Rapamune Rapamycin AY-22989
US12091424, Example 14 C16-(1,1-dioxidoisothiazolidin-2-yl)-C32-deoxo-C40-dimethylphosphinyl-rapamycin (Diastereomer 1) BDBM696419
US12091424, Example 6 C16-(1,1-dioxido-1,2-thiazetidin-2-yl)-C32-deoxo-rapamycin (Diastereomer 1) US20250223297, Example 6 BDBM696416
US20250223297, Example 10 US12091424, Example 10 BDBM696418 C16-(1,1-dioxido-1,2-thiazetidin-2-yl)-C32-deoxo-C40-dimethylphosphinyl-rapamycin (Diastereomer 1)
FK-506-M CHEMBL413 Rapamycin (16E,24E,26E,28E)-1,18-Dihydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-ethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.0*4,9*]hexatriaconta-16,24,26,28-tetraene-2 RAPAMYCIN IMMUNOSUPPRESSANT DRUG BDBM50068561 WY-090217 Rapamune Sirolimus analogue AY-22989 1,18-Dihydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-ethyl]-19,30,33-trimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.0*4,9*]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone;Rapamycin 1,18-dihydroxy-12-{2-[4-hydroxy-3-methoxy-(4R)-cyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone SIROLIMUS