Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3)

Abdellah Yamani; Daria Zdżalik-Bielecka; Joanna Lipner; Aleksandra Stańczak; Natalia Piórkowska; Paulina Seweryna Stańczak; Patrycja Olejkowska; Joanna Hucz-Kalitowska; Marta Magdycz; Karolina Dzwonek; Krzysztof Dubiel; Monika Lamparska-Przybysz; Delfina Popiel; Jerzy Pieczykolan; Maciej Wieczorek

doi:10.1016/j.ejmech.2020.112990

Discovery and optimization of novel pyrazole-benzimidazole CPL304110, as a potent and selective inhibitor of fibroblast growth factor receptors FGFR (1-3)

Eur J Med Chem. 2021 Jan 15:210:112990. doi: 10.1016/j.ejmech.2020.112990. Epub 2020 Nov 7.

Authors

Abdellah Yamani¹, Daria Zdżalik-Bielecka², Joanna Lipner³, Aleksandra Stańczak⁴, Natalia Piórkowska³, Paulina Seweryna Stańczak², Patrycja Olejkowska³, Joanna Hucz-Kalitowska², Marta Magdycz³, Karolina Dzwonek², Krzysztof Dubiel³, Monika Lamparska-Przybysz², Delfina Popiel², Jerzy Pieczykolan², Maciej Wieczorek⁴

Affiliations

¹ Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland. Electronic address: [email protected].
² Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland.
³ Celon Pharma S.A., Medicinal Chemistry Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland.
⁴ Celon Pharma S.A., Preclinical Development Department, Mokra 41A, Kiełpin, 05-092, Łomianki, Poland; Celon Pharma S.A., Clinical Trials Department, Ogrodowa 2A, Kiełpin, 05-092, Łomianki, Poland.

PMID: 33199155
DOI: 10.1016/j.ejmech.2020.112990

Abstract

The FGFR family is characterized by four receptors (FGFR 1-4), binding to 18 ligands called fibroblast growth factors (FGFs). Aberrant activation of FGFs and their FGFRs has been implicated in a broad spectrum of human tumors. We employed the scaffolds hybridization approach, scaffold-hopping concept to synthesize a series of novel pyrazole-benzimidazole derivatives 56 (a-x). Compound 56q (CPL304110) was identified as a selective and potent pan-FGFR inhibitor for FGFR1, -2, -3 with IC₅₀s of 0.75 nM, 0.50 nM, 3.05 nM respectively, whereas IC₅₀ of 87.90 nM for FGFR4. Due to its favorable pharmacokinetic profile, low toxicity and potent anti-tumor activity in vivo, compound 56q is currently under evaluation in phase I clinical trial for the treatment of bladder, gastric and squamous cell lung cancers (01FGFR2018; NCT04149691).

Keywords: Anti-tumor activity; FGFR (1–3) inhibitor; Pyrazole-benzimidazole.

Publication types

Review

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Cell Proliferation / drug effects
Drug Discovery*
Humans
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 2 / metabolism
Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 3 / metabolism

Substances

Antineoplastic Agents
Benzimidazoles
Protein Kinase Inhibitors
Pyrazoles
pyrazole
benzimidazole
FGFR1 protein, human
FGFR2 protein, human
FGFR3 protein, human
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Fibroblast Growth Factor, Type 2
Receptor, Fibroblast Growth Factor, Type 3

Associated data

ClinicalTrials.gov/NCT04149691