Abstract 1847: Phenotypic evaluation and discrimination of clinical JAK inhibitors for myeloproliferative disorders

Abstract

Abstract Small molecule inhibitors of Janus kinases (Jakinibs) represent a promising treatment for myeloproliferative disorders including polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF). Currently multiple JAK2 inhibitors (ruxolitinib, fedratinib, momelotinib, baricitinib) are either approved or in clinical development for the treatment of MF. The primary target of Jakinibs, the JAK-STAT pathway, plays a critical role in multiple cellular processes relevant for myelofibrosis, including survival, differentiation, and proliferation. However, all approved Jakinibs are reportedly promiscuous in that they inhibit kinases beyond the JAK family. Their overall clinical impact, therefore, reflects the sum of these target activities, as well as downstream secondary pharmacology relevant to both efficacy and safety. We evaluated these four Jakinibs using phenotypic profiling with the BioMAP® Diversity PLUS Panel to identify common versus differential activities. The BioMAP platform consists of human primary cell-based assay or systems designed to recapitulate key aspects of tissue and disease states. Distinct activity profiles were generated for each of the tested Jakinibs based on their impacts on 148 different biomarkers in 12 different model systems. Comparison of these profiles at concentrations relevant for clinical exposure levels revealed common activities including inhibition of T and B cell proliferation and decreased levels of inflammation and immune activation biomarkers. Together these activities represent a phenotypic signature related to shared primary JAK targets. In contrast, multiple differentiating activities were observed between the four drug profiles: baricitinib increased TNFα levels whereas momelotinib decreased TNFα in the LPS system modeling monocyte activation; fedratinib and momelotinib, but not ruxolitinib or baricitinib, inhibited endothelial cell proliferation; only momelotinib inhibited macrophage responses and decreased PGE2 levels. These data indicate that even within the specific JAK2 inhibitor drug class, individual entities have distinct modes of action relevant for clinical outcomes. Citation Format: Sharlene Velichko, Sheryl P. Denker, Alison O'Mahony. Phenotypic evaluation and discrimination of clinical JAK inhibitors for myeloproliferative disorders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1847.