Targeting mutated MYD88 pro-survival signaling in B-cell malignancies
Steven Treon
MD PhDDana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2026
Our laboratory and those of others discovered highly recurring mutations in the gene MYD88 which are found in patients with various B-cell cancers including Waldenstrom’s Macroglobulinemia (95-97%), ABC Subtype of Diffuse B-cell Lymphoma (30-40%), Primary Central Nervous Lymphoma (80%), Marginal Zone Lymphoma (10%) and Chronic Lymphocytic Leukemia (5-10%). Our laboratory and those of others showed that mutated MYD88 triggers BTK, which is the target of BTK-inhibitors like ibrutinib, acalabrutinib and zanubrutinib though complete remissions are rare with these agents largely in part because other pro-survival molecules are activated by mutated MYD88 such as HCK and IRAK1. In these studies, we will develop potent and selective inhibitors to HCK and IRAK1, including PROTACs which inhibit and degrade these molecules, using lead molecules and scaffolds whose target selectivity and activity we previously validated. We will also investigate the mechanisms underlying the inactivation of the Inhibitor of BTK (IBTK) as a potential new target for development of inhibitors for use in MYD88 mutated lymphomas.
MYD88 is mutated in many B-cell cancers including Waldenstrom's Macroglobulinemia (WM), certain aggressive lymphomas, including those that can infiltrate the brain, marginal zone lymphoma, and chronic lymphocytic leukemia. In our previous studies, we found that MYD88 turned on BTK, which drives activation of B-cells. This finding led to the development of BTK inhibitors for WM leading to the first ever approval in WM of a drug (ibrutinib) and subsequently zanubrutinib. Despite the highly active nature of these drugs in WM and other B-cell cancers driven by mutated MYD88, complete remissions are rare, and patients can exhibit both primary (initial) resistance and acquired resistance which occurs later in time after patients respond. In primary resistance, an alternative switch mediated by IRAK1 keeps MYD88 mutated lymphoma cells alive. Hence, developing inhibitors that target IRAK1 may synergistically act with BTK inhibitors and overcome primary resistance in MYD88 mutated lymphoma cells. In previous work, we developed the first ever potent and selective IRAK1 inhibitor JHX-119-01 with our medicinal chemistry colleagues at Harvard Medical School. We tested this agent, which blocked IRAK1 activity and showed high levels of synergy with the BTK-inhibitor ibrutinib. It also shutdown the survival signals for mutated MYD88 better than either agent alone. However, the molecule was not absorbed from the gut in animal studies. We therefore propose as part of these studies to continue our development of an orally active potent and selective IRAK1 inhibitor. We have identified an initial candidate, PS-IV-91, which shows increased oral bioavailability (F=11%) and synergy with ibrutinib. We will develop additional analogues with a higher absorption rate (30-50%), and better tumor cell penetration. We will also use PROTAC technology to put a warhead on the lead drug that tags the IRAK1 protein and leads it to cellular wastebaskets for disposal. Our medicinal chemistry team is particularly suited for this effort since they were involved in the initial PROTAC scientific breakthroughs and retain the needed expertise for the development of such agents. We will also do pharmacological assessment of the candidate drugs in animal studies. We will also pursue development of PROTACs for HCK. In previous work, we showed that mutated MYD88 driven lymphomas have increased levels of HCK. HCK turns on many survival switches that keep MYD88 driven lymphomas alive. We developed a lead HCK inhibitor, KIN-8194, that showed remarkable activity in mice engrafted with aggressive MYD88 mutated lymphoma cells. Half of all mice showed no lymphomas after 6 weeks of treatment. KIN-8194 was also highly active in ibrutinib resistant lymphoma cells bearing a mutation to the binding site for ibrutinib on BTK. Lastly, we will further probe for other vulnerabilities related to BTK regulation in MYD88 mutated lymphomas and will seek to develop drug strategies based on these revelations