Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1 PMID: 27155900

ADC Targets in Oncology

2026-04-10

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1

Bioorg Med Chem Lett. 2016 Jun 15;26(12):2774-2778. doi: 10.1016/j.bmcl.2016.04.073.

Zacharia Cheruvallath ¹ , Mingnam Tang ¹ , Christopher McBride ¹ , Mallareddy Komandla ¹ , Joanne Miura ¹ , Thu Ton-Nu ¹ , Phil Erikson ¹ , Jun Feng ¹ , Pamela Farrell ² , J David Lawson ³ , Darin Vanderpool ² , Yiqin Wu ² , Douglas R Dougan ⁴ , Artur Plonowski ² , Corine Holub ² , Chris Larson ²

Affiliations

Abstract

Methionine Aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.

Keywords

FBDD; Fragment-based drug discovery; Indazole; MetAP2; Metalloprotease; Methionine aminopeptidase 2.