PAK4-IN-1 (KPT-9274) is a first-in-class, orally bioavailable, small molecule immunometabolic modulator that works through non-competitive dual inhibition of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). Co-inhibition of these targets is believed to lead to synergistic anti-tumor effects through suppression of ß-catenin by blocking PAK4, leading to both immune cell activation and inhibition of tumor growth, energy depletion through NAMPT inhibition, blockade of DNA repair, cell cycle arrest and ultimately apoptosis. KPT-9274 may therefore have both immune-activating and direct antitumor effects. In contrast, normal cells are less sensitive to inhibition by KPT-9274 due in part to their relative genomic stability and lower metabolic demands. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. Oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC.

Piraxelate is the pyrrolidone acetamide derivative. It was developed as a smooth muscle relaxant.