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

被引：38

作者：

Yamani, Abdellah ^{[1
]}

Zdzalik-Bielecka, Daria ^{[2
,5
]}

Lipner, Joanna ^{[1
,6
]}

Stanczak, Aleksandra ^{[2
,3
]}

Piorkowska, Natalia ^{[1
]}

Stanczak, Paulina Seweryna ^{[2
,7
]}

Olejkowska, Patrycja ^{[1
]}

Hucz-Kalitowska, Joanna ^{[2
]}

Magdycz, Marta ^{[1
,6
]}

Dzwonek, Karolina ^{[2
]}

Dubiel, Krzysztof ^{[1
]}

Lamparska-Przybysz, Monika ^{[2
,4
]}

Popiel, Delfina ^{[2
]}

Pieczykolan, Jerzy ^{[2
]}

Wieczorek, Maciej ^{[2
,3
]}

机构：

[1] Celon Pharma SA, Med Chem Dept, Mokra 41A, PL-05092 Kielpin, Lomianki, Poland

[2] Celon Pharma SA, Preclin Dev Dept, Mokra 41A, PL-05092 Kielpin, Lomianki, Poland

[3] Celon Pharma SA, Clin Trials Dept, Ogrodowa 2A, PL-05092 Kielpin, Lomianki, Poland

[4] Polpharma, Bobrowiecka 6, PL-00728 Warsaw, Poland

[5] Int Inst Mol & Cell Biol, Lab Cell Biol, Warsaw, Poland

[6] Pikralida Sp Zoo, Bukowska 70, PL-60812 Poznan, Poland

[7] OncoArendi Therapeut, Zwirki & Wigury 101, Warsaw, Poland

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 210卷

关键词：

Anti-tumor activity; FGFR (1-3) inhibitor; Pyrazole-benzimidazole; TYROSINE KINASE INHIBITOR; BREAST-CANCER; MUTATIONS; FAMILY; JNJ-42756493; ERDAFITINIB; DERIVATIVES; ABERRATIONS; ACTIVATION; PROGNOSIS;

D O I：

10.1016/j.ejmech.2020.112990

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 IC(50)s 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). (C) 2020 Elsevier Masson SAS. All rights reserved.

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