Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors

Pyruvate
dehydrogenase kinases (PDKs) are overexpressed in most cancer cells
and are responsible for aberrant glucose metabolism. We previously
described bis­(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of
the scaffold of 16, we identify two novel types of disulfide-based
PDK1 inhibitors. The most potent analogue, 3a, effectively
inhibits PDK1 both at the molecular (kinact/Ki = 4.17 × 103 M–1 s–1) and the cellular level (down
to 0.1 μM). In contrast to 16, 3a is
a potent and subtype-selective inhibitor of PDK1 with >40-fold
selectivity for PDK2–4. 3a also significantly
alters glucose metabolic pathways in A549 cells by decreasing ECAR
and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to
the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as
a first-generation subtype-selective and covalent PDK1 inhibitor.