title: Drug discovery considerations in the development of covalent inhibitors.
abstract: In recent years, the number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the technical challenges for characterizing and optimizing these inhibitors have become evident. A number of new tools have been developed to aid this process, but these have not gained wide-spread use. This review will highlight a number of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.
authors: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research, Klybeckstrasse 141, CH-4057 Basel, Switzerland.
authors: Robert
authors: R
authors: Mah
authors: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors: Jason R
authors: JR
authors: Thomas
authors: Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, CA 94608, USA. Electronic address: cynthia.shafer@novartis.com.
authors: Cynthia M
authors: CM
authors: Shafer
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D004798:Enzymes
keywords: Activity-based protein profiling (ABPP); Click chemistry; Covalent inhibitor; Mechanism-based inhibitor; Targeted covalent inhibitor (TCI); Warhead reactivity; k(inact)/K(i)