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.

Aminoquinuride (Surfen) binds to glycosaminoglycans (GAGs) and has been shown to influence their function, and the function of proteoglycans (complexes of GAGs linked to a core protein). Surfen was first described in 1938 as a component of depot insulin; however, subsequent studies have revealed its efficacy in binding to glycosaminoglycans (GAGs). Surfen contains four quinoline rings that contain positively charged amino or methyl groups. Surfen was found to bind with greatest avidity to heparin. There are now a handful of studies on the biological effects of surfen, many of which relate to its ability to block the interaction between GAGs and signaling proteins, including effects on growth factors (fibroblast growth factor and vascular endothelial growth factor) and fibrils associated with the binding of human immunodeficiency virus (HIV)-1 to target cells. Surfen inhibits the action of SEVI (semen-derived enhancer of HIV viral infection). Because SEVI can increase HIV infectivity by several orders of magnitude, supplementing current HIV microbicide candidates with SEVI inhibitors, such as surfen, might greatly increase their potency. Surfen has also been shown to reduce inflammation but inhibits remyelination in murine models of multiple sclerosis.

Exisulind (tentative trade name Aptosyn) is an antineoplastic agent, which was originally developed by Cell Pathways. This drug is an inhibitor of phosphodiesterase (PDE) isozymes: PDE5 and PDE4. Inhibition of PDE5 appears to be pharmacologically relevant, which leads to increase cGMP and activate protein kinase G at doses that induce apoptosis, whereas cyclic AMP levels were not changed. Exisulind has been in phase III clinical trials for the treatment of Non-Small Cell Lung Cancer and for the treatment of polyps in patients who have familial adenomatous polyposis (Colorectal Cancer and Small Intestine Cancer). In addition, this drug was in phase II/III for the treatment of Prostate Cancer, however, there studies have been discontinued.