Degrasyn-like symmetrical compounds: possible therapeutic agents for multiple myeloma (MM-I)

Zhenghong Peng; David S Maxwell; Duoli Sun; Basvoju A Bhanu Prasad; Paul T Schuber Jr; Ashutosh Pal; Yunming Ying; Dongmei Han; Liwei Gao; Shimei Wang; Alexander Levitzki; Vaibhav Kapuria; Moshe Talpaz; Matthew Young; Hollis D Showalter; Nicholas J Donato; William G Bornmann

doi:10.1016/j.bmc.2013.12.048

Degrasyn-like symmetrical compounds: possible therapeutic agents for multiple myeloma (MM-I)

Bioorg Med Chem. 2014 Feb 15;22(4):1450-8. doi: 10.1016/j.bmc.2013.12.048. Epub 2014 Jan 3.

Authors

Zhenghong Peng¹, David S Maxwell¹, Duoli Sun¹, Basvoju A Bhanu Prasad¹, Paul T Schuber Jr¹, Ashutosh Pal², Yunming Ying², Dongmei Han², Liwei Gao², Shimei Wang², Alexander Levitzki³, Vaibhav Kapuria⁴, Moshe Talpaz⁴, Matthew Young⁵, Hollis D Showalter⁶, Nicholas J Donato⁴, William G Bornmann⁷

Affiliations

¹ Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States.
² Department of Experimental Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States.
³ Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁴ Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine, Comprehensive Cancer Center, United States.
⁵ Department of Pharmacology, University of Michigan School of Medicine, Comprehensive Cancer Center, United States.
⁶ Department of Medicinal Chemistry, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, United States.
⁷ Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States. Electronic address: wbornmann@mdanderson.org.

Abstract

A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.

Keywords: Degrasyn; Inhibitors; Jak2/Stat3; Multiple myeloma; Small molecules; Synthesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / therapeutic use
Antineoplastic Agents / toxicity
Cell Line, Tumor
Cell Survival / drug effects
Cyanoacrylates
Dimerization
Humans
Models, Molecular
Multiple Myeloma / drug therapy
Nitriles / chemistry*
Nitriles / pharmacology
Nitriles / therapeutic use
Pyridines / chemistry*
Pyridines / pharmacology
Pyridines / therapeutic use
Ubiquitin Thiolesterase / antagonists & inhibitors
Ubiquitin Thiolesterase / metabolism

Substances

Antineoplastic Agents
Cyanoacrylates
Nitriles
Pyridines
USP9X protein, human
degrasyn
Ubiquitin Thiolesterase

Abstract

Publication types

MeSH terms

Substances

Grants and funding