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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-152149

CTP Synthetase-IN-1

99.56%, CTP Synthetase Inhibitor

DNA/RNA Synthesis

Inflammation/Immunology

Name
Email *

	Sorry, but the email address you supplied was invalid.