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.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.48 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

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).

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.

(2018) J Med Chem 61: 8226-8240

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00690
  • Primary Citation of Related Structures:  
    6H3K

  • 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.


  • Organizational Affiliation

    Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SM2 5NG , United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity protein kinase TTK279Homo sapiensMutation(s): 0 
Gene Names: TTKMPS1MPS1L1
EC: 2.7.12.1
UniProt & NIH Common Fund Data Resources
Find proteins for P33981 (Homo sapiens)
Explore P33981 
Go to UniProtKB:  P33981
PHAROS:  P33981
GTEx:  ENSG00000112742 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP33981
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FMW
Query on FMW

Download Ideal Coordinates CCD File 
B [auth A]~{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
C24 H30 N8 O
SGWLRDAOCLITOM-UHFFFAOYSA-N
7PE
Query on 7PE

Download Ideal Coordinates CCD File 
C [auth A]2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL
C14 H30 O7
UKXKPKBTMYNOFS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FMW BindingDB:  6H3K Ki: 0.11 (nM) from 1 assay(s)
IC50: min: 3, max: 63 (nM) from 3 assay(s)
Binding MOAD:  6H3K Ki: 1.10e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.48 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.209 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.624α = 90
b = 107.644β = 90
c = 114.683γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
United Kingdom--

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-19
    Type: Initial release
  • Version 1.1: 2018-10-10
    Changes: Data collection, Database references