6H3K

Introduction of a methyl group curbs metabolism of pyrido[3,4-d]pyrimidine MPS1 inhibitors and enables the discovery of the Phase 1 clinical candidate BOS172722.

6H3K の概要

• エントリーDOI: 10.2210/pdb6h3k/pdb
• 分子名称: Dual specificity protein kinase TTK, ~{N}8-(2,2-dimethylpropyl)-~{N}2-[2-ethoxy-4-(4-methyl-1,2,4-triazol-3-yl)phenyl]-6-methyl-pyrido[3,4-d]pyrimidine-2,8-diamine, 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL, ... (4 entities in total)
• 機能のキーワード: kinase, spindle assembly checkpoint, mitosis, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33002.02

構造登録者

Woodward, H.L.,Hoelder, S. (登録日: 2018-07-19, 公開日: 2018-09-19, 最終更新日: 2024-05-15)

主引用文献

Woodward, H.L.,Innocenti, P.,Cheung, K.J.,Hayes, A.,Roberts, J.,Henley, A.T.,Faisal, A.,Mak, G.W.,Box, G.,Westwood, I.M.,Cronin, N.,Carter, M.,Valenti, M.,De Haven Brandon, A.,O'Fee, L.,Saville, H.,Schmitt, J.,Burke, R.,Broccatelli, F.,van Montfort, R.L.M.,Raynaud, F.I.,Eccles, S.A.,Linardopoulos, S.,Blagg, J.,Hoelder, S.
Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722).
J. Med. Chem., 61:8226-8240, 2018

PubMed Abstract: Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4- d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4- d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.

PubMed: 30199249
DOI: 10.1021/acs.jmedchem.8b00690

実験手法

X-RAY DIFFRACTION (2.48 Å)