Discovery of Selective, Orally Bioavailable Pyrazolopyridine Inhibitors of Protein Kinase Cθ (PKCθ) That Ameliorate Symptoms of Experimental Autoimmune Encephalomyelitis PMID: 31417666

ADC Targets in Oncology

2026-04-10

Discovery of Selective, Orally Bioavailable Pyrazolopyridine Inhibitors of Protein Kinase Cθ (PKCθ) That Ameliorate Symptoms of Experimental Autoimmune Encephalomyelitis

ACS Med Chem Lett. 2019 Jun 27;10(8):1134-1139. doi: 10.1021/acsmedchemlett.9b00134.

Philip N Collier ¹ , Heather C Twin ² ¹ , Ronald M A Knegtel ² ¹ , Dean Boyall ² ¹ , Guy Brenchley ² ¹ , Christopher J Davis ² ¹ , Shazia Keily ² ¹ , Chau Mak ² ¹ , Andrew Miller ² ¹ , Françoise Pierard ² ¹ , Luca Settimo ² ¹ , Clare M Bolton ² ¹ , Peter Chiu ² ¹ , Adam Curnock ² ¹ , Elisabeth Doyle ¹ , Adam J Tanner ² ¹ , Juan-Miguel Jimenez ² ¹

Affiliations

Abstract

PKCθ plays an important role in T Cell Biology and is a validated target for a number of disease states. A series of potent and selective PKCθ inhibitors were designed and synthesized starting from a HTS hit compound. Cell activity, while initially a challenge to achieve, was built into the series by transforming the nitrile unit of the scaffold into a primary amine, the latter predicted to form a new hydrogen bond to Asp508 near the entrance of the ATP binding site of PKCθ. Significant improvements in physiochemical parameters were observed on introduction of an oxetane group proximal to a primary amine leading to compound 22, which demonstrated a reduction of symptoms in a mouse model of multiple sclerosis.