Discovery and Optimization of Potent and Orally Available CTP Synthetase Inhibitors for Use in Treatment of Diseases Driven by Aberrant Immune Cell Proliferation

  • J Med Chem. 2022 Dec 22;65(24):16640-16650. doi: 10.1021/acs.jmedchem.2c01446.
Andrew Novak  1 ,  David Laughton  1 ,  Rebecca Lane  1 ,  Emma Blackham  1 ,  Jennifer Thomas  1 ,  Elli Chatzopoulou  1 ,  Joseph Wrigglesworth  1 ,  Abdul Quddus  1 ,  Saleh Ahmed  1 ,  David Cousin  1 ,  Lorna Duffy  1 ,  Nathalie Dubois  1 ,  John Unitt  1 ,  Katalin Orban  1 ,  Edward Browne  1 ,  Michelle Ward  1 ,  David Mycock  1 ,  Maria Ieva  1 ,  Nicholas Bland  1 ,  Pascal George  2 ,  Timothy Bourne  2 ,  Hélène Asnagli  2 ,  Louise Birch  1 ,  Geraint Jones  1
Affiliations
  • 1. Sygnature Discovery, BioCity, Pennyfoot Street, NottinghamNG1 1GF, U.K.
  • 2. Step Pharma, 15 Rue Louis et Auguste Lumière, Saint Genis-Pouilly01 630, France.
PMID: 36449304 DOI: 10.1021/acs.jmedchem.2c01446
Abstract

Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical Enzymes in the de novo pyrimidine synthesis pathway. Weak inhibitors identified from a high-throughput screening of 240K compounds have been optimized to a potent, orally active agent, compound 27, which has shown significant pharmacological responses at 10 mg/kg dose BID in a well-established animal model of inflammation.

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