Abstract 6366: A novel small molecule inhibitor of MAPK and PI3K ameliorates disease phenotypes in myelofibrosis

Abstract

Abstract Myelofibrosis is a myeloproliferative neoplasm (MPN) caused primarily by mutations in hematopoietic stem and progenitor cells (HSPCs) that activate Janus kinase 2 (JAK2). Central roles for JAK2 signaling in myelofibrosis (MF) have been established, leading to marked extramedullary hematopoiesis, splenomegaly, and bone marrow fibrosis, but the use of JAK inhibitors has shown limited ability to produce durable remissions in most patient populations. Bypass or resistance mechanisms to JAK inhibition have been linked to concomitant activation of compensatory phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways, and while genetic and functional studies have not fully defined the mechanisms for transformation and maintenance of the proliferative state in MF, targeting multiple signaling pathways will be required to alter the disease course and improve therapeutic outcomes. Treatments using kinase inhibitor combinations remain a challenge clinically, and trials have struggled to create positive balance between gains in survival, therapeutic efficacy, and dose-limiting toxicity. A multi-functional kinase inhibitor was developed to deliver consistent and synergistic dosing ratios against multiple targets simultaneously, thereby blocking compensatory oncogenic signaling pathways while minimizing the prospect for adverse effects. Using synthetic medicinal chemistry, we present a potent and selective, orally bioavailable, single-molecule multi-targeted kinase inhibitor (LP-182) against MAPK and PI3K/mTOR signaling pathways. We demonstrate selectivity and therapeutic efficacy through in vitro screening of kinome inhibition, reduction of cell growth and downstream kinase activation, renormalization of immune cell populations, amelioration of splenomegaly and bone marrow fibrosis, and improved survival in the myeloproliferative leukemia oncogene (MPLW515L) mouse model of myelofibrosis. Furthermore, treatment with LP-182 was well tolerated showing no observable pharmacotoxicity, and combination with the JAK inhibitor Ruxolitinib also showed ~35% reduction in spleen size as compared to either treatment alone with a ~60% spleen volume reduction compared to vehicle treatment, in the JAK2+/V617F mutant mouse model. Overall, these data suggest that in vivo bioavailability and distribution of LP-182 to secondary lymphoid tissues attenuates MAPK and PI3K signaling to alleviate disease phenotypes in animal models of MF. Simultaneous targeting of both MAPK and PI3K pathways with LP-182 alone or in combination with JAK inhibition provides the potential for significant new opportunities to improve the clinical outcome of MF patients. Citation Format: Christopher A. Bonham, Youngsoon Jang, Kevin Heist, Amanda Welton, Tanner Robison, Kathryn E. Luker, Gary D. Luker, Winston Y. Lee, Thomas L. Chenevert, Marcian Van Dort, Brian D. Ross. A novel small molecule inhibitor of MAPK and PI3K ameliorates disease phenotypes in myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6366.