Development of Inhibitors of PIP4K2 As a Treatment for Patients with Hematologic Malignancies (2018)

Abstract Phosphoinositide signaling is central to many cellular processes including the cell survival pathway known as autophagy. While there is evidence that autophagy can suppress tumorigenesis under certain circumstances, there is increasingly abundant evidence that autophagy promotes tumorigenesis and tumor cell survival in solid tumors and hematologic malignancies. Autophagy is a complex process that has evolved to promote survival of cells under a variety of stress or nutrient starvation conditions. There are a multitude of molecules and structures involved in initiating, promoting, and resolving the autophagy process. It is known that PI5P is an important component for the resolution of autophagy. PIP4K2α,β,γ are a family of lipid kinases that convert PI5P to PI(4,5)P2. These enzymes have recently been shown to be critical for the fusion of autophagosomes with lysosomes. This known activity, coupled with the observation that PIP4K2 activity is essential for the survival and leukemia initiating potential of human and mouse acute myeloid leukemia (AML) cells, suggest that the PIP4K2 family of enzymes may be a promising target for a new class of therapeutics for the treatment of hematologic malignancies. We have investigated the role of PIP4K2 enzymes in supporting the survival of cancer cells by developing potent and selective inhibitors of PIP4K2 enzymatic activity. A screen of human cancer cell lines show that potent and selective inhibitors of PIP4K2 are effective at inhibiting growth of a variety of hematologic cancers including leukemia- and lymphoma-derived lines. In vivo studies demonstrate that these inhibitors induce rapid regression of an AML tumor (MOLM-16) in a mouse xenograft model. These studies show a dose-dependent control of tumor growth with sustained regression of tumor volume with QD oral dosing of a prototype molecule. Body weights of the mice were stable over the course of the study suggesting that the molecule is well tolerated in this dosing protocol. A preliminary toxicity study in rats has not revealed any identifiable toxicity at doses up to 100 mg/Kg given QD/PO for 14 days. Additional in vitro safety studies suggest minimal safety concerns due to off-target activity. Exploration of the structure activity relationship of PIP4K2 inhibitors, using fragment and structure-based drug discovery, has led to highly potent and selective molecules with exceptional drug-like properties. A clinical development candidate has been selected and that candidate is currently in the late stages of preclinical studies preceding anticipated clinical entry in early 2019. Disclosures McElligott: Petra Pharma: Employment, Equity Ownership. Kesicki:Petra Pharma: Employment, Equity Ownership. Karukarichi:Petra Pharma: Employment, Equity Ownership. Shim:Petra Pharma: Employment, Equity Ownership. Wang:Petra Pharma: Employment, Equity Ownership. Yu:Petra Pharma: Employment, Equity Ownership. Zolfaghari:Petra Pharma: Employment, Equity Ownership. Linstrom:Sprint Bioscience: Employment, Equity Ownership. Persson:Sprint Bioscience: Employment, Equity Ownership. Hoglund:Sprint Bioscience: Employment, Equity Ownership. Ericsson:Sprint Bioscience: Employment, Equity Ownership. Trésaugues:Sprint Bioscience: Employment, Equity Ownership. Livendahl:Sprint Bioscience: Employment, Equity Ownership. Santangelo:Sprint Bioscience: Employment, Equity Ownership. Viklund:Sprint Bioscience: Employment, Equity Ownership. Pettersson:Sprint Bioscience: Employment, Equity Ownership. Wähling:Sprint Bioscience: Employment, Equity Ownership. Forsblom:Sprint Bioscience: Employment, Equity Ownership. Karlsson:Sprint Bioscience: Employment, Equity Ownership. Ginman:Sprint Bioscience: Employment, Equity Ownership. Braga:Sprint Bioscience: Employment, Equity Ownership. Henley:Sprint Bioscience: Employment, Equity Ownership. Talagas:Sprint Bioscience: Employment, Equity Ownership. Rahm:Sprint Bioscience: Employment, Equity Ownership. Johansson:Sprint Bioscience: Employment, Equity Ownership. Martinsson:Sprint Bioscience: Employment, Equity Ownership. Andersson:Sprint Bioscience: Employment, Equity Ownership. Cantley:Petra Pharma: Equity Ownership.