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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..

DOI: 10.1021/acs.jmedchem.8b00690 DOI Help

Authors: Hannah L. Woodward (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Paolo Innocenti (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Kwai-ming J. Cheung (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Angela Hayes (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Jennie Roberts (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Alan T. Henley (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Amir Faisal (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Grace Wing-yan Mak (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Gary Box (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Isaac M. Westwood (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Nora Cronin (The Institute of Cancer Research) , Michael Carter (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Melanie Valenti (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Alexis De Haven Brandon (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Lisa O’fee (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Harry Saville (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Jessica Schmitt (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Rosemary Burke (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Fabio Broccatelli (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Rob L. M. Van Montfort (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Florence I. Raynaud (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Suzanne A. Eccles (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Spiros Linardopoulos (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research; The Breakthrough Breast Cancer Research Centre) , Julian Blagg (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research) , Swen Hoelder (Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2018
Diamond Proposal Number(s): 10088

Open Access Open Access

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.

Subject Areas: Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
acs.jmed456754756chem.pdf