Novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety for anaplastic lymphoma kinase (ALK) inhibitor

Raghavendra Achary; Gangadhar Rao Mathi; Dong Ho Lee; Chang Soo Yun; Chong Ock Lee; Hyoung Rae Kim; Chi Hoon Park; Pilho Kim; Jong Yeon Hwang

doi:10.1016/j.bmcl.2017.03.073

Novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety for anaplastic lymphoma kinase (ALK) inhibitor

Bioorg Med Chem Lett. 2017 May 15;27(10):2185-2191. doi: 10.1016/j.bmcl.2017.03.073. Epub 2017 Mar 29.

Authors

Raghavendra Achary¹, Gangadhar Rao Mathi¹, Dong Ho Lee², Chang Soo Yun³, Chong Ock Lee⁴, Hyoung Rae Kim³, Chi Hoon Park¹, Pilho Kim⁵, Jong Yeon Hwang⁶

Affiliations

¹ Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
² Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
³ Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
⁴ Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
⁵ Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: pkim@krict.re.kr.
⁶ Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: jyhwang@krict.re.kr.

PMID: 28385505
DOI: 10.1016/j.bmcl.2017.03.073

Abstract

In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, 28, 29, 36, and 42 showed promising anti-ALK activities in enzymatic- and cell-based assays. In vivo H3122 xenograft model study showed that compound 29 effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.

Keywords: 2,4-Diaminopyrimidine; Anaplastic lymphoma kinase; Cancer; Fused tricyclic moiety.

MeSH terms

Administration, Oral
Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / therapeutic use
Antineoplastic Agents / toxicity
Carcinoma, Non-Small-Cell Lung / drug therapy
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
Inhibitory Concentration 50
Lung Neoplasms / drug therapy
Mice
Mice, SCID
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / therapeutic use
Protein Kinase Inhibitors / toxicity
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / therapeutic use
Pyrimidines / toxicity
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Transplantation, Heterologous

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
2,4-diaminopyrimidine
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases