Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H)

Katsuhiko Sekimata; Tomohiro Sato; Naoki Sakai; Hisami Watanabe; Chiemi Mishima-Tsumagari; Tomonori Taguri; Takehisa Matsumoto; Yoshifumi Fujii; Noriko Handa; Teruki Honma; Akiko Tanaka; Mikako Shirouzu; Shigeyuki Yokoyama; Kohei Miyazono; Yoshinobu Hashizume; Hiroo Koyama

doi:10.1248/cpb.c18-00598

Current Topics: Regular Articles

Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H)

Katsuhiko Sekimata , Tomohiro Sato, Naoki Sakai, Hisami Watanabe, Chiemi Mishima-Tsumagari, Tomonori Taguri, Takehisa Matsumoto, Yoshifumi Fujii, Noriko Handa, Teruki Honma, Akiko Tanaka, Mikako Shirouzu, Shigeyuki Yokoyama, Kohei Miyazono, Yoshinobu Hashizume, Hiroo Koyama

Author information

Katsuhiko Sekimata Corresponding author
Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science
Tomohiro Sato
Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research
Naoki Sakai
Drug Discovery Structural Biology Platform Unit, RIKEN Biosystems Dynamics Research
Hisami Watanabe
Drug Discovery Structural Biology Platform Unit, RIKEN Biosystems Dynamics Research
Chiemi Mishima-Tsumagari
Drug Discovery Structural Biology Platform Unit, RIKEN Biosystems Dynamics Research
Tomonori Taguri
Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science
Takehisa Matsumoto
Drug Discovery Structural Biology Platform Unit, RIKEN Biosystems Dynamics Research
Yoshifumi Fujii
Crystallographic Drug Discovery Platform Unit, RIKEN Systems and Structural Biology Center
Noriko Handa
Crystallographic Drug Discovery Platform Unit, RIKEN Systems and Structural Biology Center
Teruki Honma
Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research
Akiko Tanaka
Drug Discovery Structural Biology Platform Unit, RIKEN Biosystems Dynamics Research
Mikako Shirouzu
Drug Discovery Structural Biology Platform Unit, RIKEN Biosystems Dynamics Research
Shigeyuki Yokoyama
Crystallographic Drug Discovery Platform Unit, RIKEN Systems and Structural Biology Center
Kohei Miyazono
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo
Yoshinobu Hashizume
RIKEN Program for Drug Discovery and Medical Technology Platforms
Hiroo Koyama
Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science

Keywords: fibrodysplasia ossificans progressiva, activin receptor-like kinase-2, inhibitor

JOURNAL FREE ACCESS FULL-TEXT HTML

2019 Volume 67 Issue 3 Pages 224-235

DOI https://doi.org/10.1248/cpb.c18-00598

Details

Abstract

Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure–activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.

Graphical Abstract Fullsize Image

Corresponding author

Register with J-STAGE for free!