Targeting mutated MYD88 signaling in B-cell malignancies

MYD88 mutations are commonly found in Waldenstrom’s Macroglobulinemia (95-97%), primary CNS lymphoma (80%), ABC subtype of diffuse large B-cell lymphoma (40%); marginal zone lymphoma (10%); and chronic lymphocytic leukemia (10%). Mutated MYD88 can drive the growth of these cancers, and blocking MYD88 signaling is fatal to these malignant cells. Our previous work identified that BTK was a critical component for mutated MYD88 signaling, a finding that enabled FDA and EMA approval of BTK-inhibitors for Waldenstrom’s Macroglobulinemia (WM). While BTK-inhibitors are highly effective, complete responses are rare, and resistance develops. We therefore have focused on the development of inhibitors that target other key elements of MYD88 signaling. In our first specific aim, we will develop and advance compounds that target IRAK1 and IRAK4. Our previous work has shown that adding IRAK-inhibitors to BTK-inhibitors can produce synergistic effects. The enzymatic (kinase) activity and the scaffold (body) of IRAK1 and IRAK4 provide distinct survival functions in response to mutated MYD88. We have developed lead compounds that inhibit the activity and degrade both IRAK1 and IRAK4, exemplified by our prototype JH-XIII-05-01. JH-XIII-05-01 has shown dynamic synergy with BTK- as well as BCL2- inhibitors in killing mutated MYD88 lymphoma cells. In our TRP proposal, we will develop and study other analogues utilizing the structure of JH-XIII-05-01 and other prototypes in MYD88 mutated lymphoma cells. For specific aim 2, we aim to address “acquired resistance” which is what occurs when patients on BTK-inhibitors develop drug resistance. Targeting HCK offers a novel means to treat BTK inhibitor resistance by blocking HCK, the kinase responsible for much of mutated MYD88 signaling including the activation of BTK. Our previous medicinal chemistry efforts funded by Blood Cancer United enabled the development of KIN-8194, a dual HCK and BTK kinase inhibitor. In our second specific aim, we will use the KIN-8194 scaffold to develop compounds that block both the kinase function and degrade the protein structure of HCK and BTK, as exemplified by our prototypes DFCI-002-05 and DFCI-002-06. We will evaluate these compounds and those produced by our medicinal chemistry efforts in BTK-resistant model systems and perform pre-clinical evaluations to advance our lead molecule for human trials. Targeting mutated MYD88 itself offers an important opportunity to abolish all pro-survival signaling regardless of BTK mutation status. In specific aim 3, we will use the structures of novel MYD88 binders that we have identified by extensive chemoproteomic screening to develop highly potent, selective, and bioavailable degraders of mutated MYD88.