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

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

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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