6C4D

Structure based design of RIP1 kinase inhibitors

Summary for 6C4D

• Entry DOI: 10.2210/pdb6c4d/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 1, (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-8-carbonitrile (3 entities in total)
• Functional Keywords: human ripk1 kinase, cell cycle, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q13546
• Total number of polymer chains: 4
• Total formula weight: 136230.65

Authors

Saikatendu, K.S.,Yoshikawa, M. (deposition date: 2018-01-11, release date: 2018-03-21, Last modification date: 2024-03-13)

Primary citation

Yoshikawa, M.,Saitoh, M.,Katoh, T.,Seki, T.,Bigi, S.V.,Shimizu, Y.,Ishii, T.,Okai, T.,Kuno, M.,Hattori, H.,Watanabe, E.,Saikatendu, K.S.,Zou, H.,Nakakariya, M.,Tatamiya, T.,Nakada, Y.,Yogo, T.
Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic Relationships.
J. Med. Chem., 61:2384-2409, 2018

PubMed Abstract: We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure-kinetic relationship (SKR) for our novel chemical series was also discussed.

PubMed: 29485864
DOI: 10.1021/acs.jmedchem.7b01647

Experimental method

X-RAY DIFFRACTION (2.52 Å)