6ACR

Crystal structure of human ALK2 kinase domain with R206H mutation in complex with RK-59638

Summary for 6ACR

• Entry DOI: 10.2210/pdb6acr/pdb
• Descriptor: Activin receptor type-1, N-(4-methoxyphenyl)-4-[3-(pyridin-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine, SULFATE ION, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, kinase, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70328.37

Authors

Sakai, N.,Mishima-Tsumagari, C.,Matsumoto, T.,Shirouzu, M. (deposition date: 2018-07-27, release date: 2019-03-20, Last modification date: 2023-11-22)

Primary citation

Sekimata, K.,Sato, T.,Sakai, N.,Watanabe, H.,Mishima-Tsumagari, C.,Taguri, T.,Matsumoto, T.,Fujii, Y.,Handa, N.,Honma, T.,Tanaka, A.,Shirouzu, M.,Yokoyama, S.,Miyazono, K.,Hashizume, Y.,Koyama, H.
Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).
Chem. Pharm. Bull., 67:224-235, 2019

PubMed 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.

PubMed: 30828000
DOI: 10.1248/cpb.c18-00598

Experimental method

X-RAY DIFFRACTION (2.01 Å)