Replacing the terminal piperidine in ceritinib with aliphatic amines confers activities against crizotinib-resistant mutants including G1202R

Gangadhar Rao Mathi; Chung Hyo Kang; Heung Kyoung Lee; Raghavendra Achary; Ha-Yeon Lee; Joo-Youn Lee; Jae Du Ha; Sunjoo Ahn; Chi Hoon Park; Chong Ock Lee; Jong Yeon Hwang; Chang-Soo Yun; Hee Jung Jung; Sung Yun Cho; Hyoung Rae Kim; Pilho Kim

doi:10.1016/j.ejmech.2016.11.046

Replacing the terminal piperidine in ceritinib with aliphatic amines confers activities against crizotinib-resistant mutants including G1202R

Eur J Med Chem. 2017 Jan 27:126:536-549. doi: 10.1016/j.ejmech.2016.11.046. Epub 2016 Nov 24.

Authors

Affiliations

¹ Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea.
² Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; College of Pharmacy, Chungnam National University, Daejeon 34134, South Korea.
³ Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
⁴ Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; College of Pharmacy, Chungbuk National University, Cheongju 28644, South Korea.
⁵ Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
⁶ Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea. Electronic address: hyungrk@krict.re.kr.
⁷ Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, South Korea. Electronic address: pkim@krict.re.kr.

PMID: 27915169
DOI: 10.1016/j.ejmech.2016.11.046

Abstract

The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound 10 shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC₅₀ of 1.8 nM. Furthermore, pharmacokinetic profiles of 10 is apparently better than that of ceritinib. In murine xenograft studies, compound 10 turns out to be as active as ceritinib, suggesting that further optimization of 10 may lead to clinical candidates overcoming ALK mutant issues.

Keywords: Anaplastic lymphoma kinase (ALK); Ceritinib; Crizotinib-resistant; G1202R; Non-small cell lung cancer (NSCLC).

MeSH terms

Amines / chemistry
Anaplastic Lymphoma Kinase
Animals
Crizotinib
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Heterografts / drug effects
Humans
Mice
Mutation
Piperidines / chemistry
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Pyrazoles* / pharmacology
Pyridines* / pharmacology
Pyrimidines / chemistry
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Receptor Protein-Tyrosine Kinases / drug effects*
Receptor Protein-Tyrosine Kinases / genetics
Sulfones / chemistry
Sulfones / pharmacokinetics
Sulfones / pharmacology*

Substances

Amines
Piperidines
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Pyrimidines
Sulfones
Crizotinib
piperidine
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases
ceritinib