Therapeutics: 3-phosphoinositide dependent protein kinase-1 (PDPK1); protein kinase B (AKT; AKT1; PKB; PKBA); ribosomal protein S6 kinase 70kDa polypeptide 1 (R

In vitro studies suggest that small molecule allosteric inhibitors of PDPK1 could enhance the anti-tumor activity of PDPK1 inhibitors to help treat cancer. The C-terminal domain of PDPK1 contains the PDPK1-interacting fragment (PIF) that is used to recruit other kinases for phosphorylation by PDPK1. Chemical synthesis and screening of small molecules identified a lead compound that bound PIF with a Kd of 1.5 μM and inhibited PDPK1-mediated phosphorylation of its S6K1 substrate by 75%. In a human cell line, the lead compound and GSK2334470, a selective ATP-competitive PDPK1 inhibitor, decreased PDPK1-induced phosphorylation of AKT and S6K compared with GSK2334470 alone. Next steps include structure-guided lead optimization and pharmacological evaluation in preclinical models.

Arno Therapeutics Inc. has AR-1, a small molecule PDPK1 inhibitor, in Phase I testing to treat solid tumors and lymphoma...