Design, synthesis, and biological evaluation of Src family SH2 domain ligands bearing a stereodiversified cis-enediol scaffold
Abstract
As an important modulator of protein tyrosine kinase signaling, the Src homology-2 (SH2) domain has emerged as an attractive drug target for various cancers and autoimmune diseases. A novel series of Src family SH2 domain ligands has been synthesized, incorporating a stereodiversified 1,4-cis-enediol scaffold. The synthetic strategy offers straightforward and highly selective access to the enediol and its associated chiral centers. Key steps include asymmetric aldol coupling, amide alkynylation, and asymmetric ketone reduction. Binding affinities to the Lck kinase SH2 domain were determined for all diastereomers by biolayer interferometry, with IC50 values ranging from 50 - 245 µM. Testing of a prodrug-conjugated ligand in a cell-based assay revealed cytotoxic activity.
Degree
Ph.D.
Advisors
Borch, Purdue University.
Subject Area
Chemistry|Pharmacy sciences
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