Abstract 5222: Degraders targeting both IRAK4 and IMiD substrates show combinatorial effects leading to broader activity with durable and complete regressions in MYD88 mutant lymphoma xenografts in vivo
Authors: Walker Duncan H. , Mayo Michele , Klaus Christine , Rong Haojing , Rusin Scott , Sharma Kirti , McDonald Alice , Campbell Veronica , Kelleher Joseph , Gollob Jared , Mainolfi Nello , Weiss Matt 
Published: September 2020

Abstract
Targeted protein degraders (TPD) are heterobifunctional small molecules that employ the ubiquitin degradation system to drive the selective degradation of target proteins. In approximately one third of B-cell lymphomas, gain of function mutations in MYD88 constitutively activate the myddosome and drive proliferation and survival through NFkB and AP1 signaling. IRAK4, is a key component of the myddosome and IRAK4 TPD show potent and selective IRAK4 degradation and preferential activity in MYD88 mutated B cell lymphoma models. Notably, the activity of IRAK4 degraders is superior to kinase inhibition, supporting the essential scaffolding role of IRAK4 in Myddosome signaling. An important goal of cancer therapy is to drive to deep and durable responses in patients, and this is frequently achieved by combination therapy. It has been suggested that blocking NFkB while simultaneously inducing a Type 1 IFN response with an IMiD (e.g. Lenalidomide Yang et al. (2012) Cancer Cell 21, 6, p723) may drive additive or synergistic antitumor activity. We have developed novel degraders that utilize an IMiD as a cereblon binder. These compounds simultaneously degrade both IRAK4 and IMiD substrates, enabling a therapeutically-relevant biological combination within a single small molecule. Here we show that dual IRAK4 and IMiD based degraders have potent antiproliferative activity across MYD88 mutant, but not MYD88WT lymphoma cell lines, with increased and broader antiproliferative and apoptosis activity relative to selective IRAK4 degraders or IMiDs alone. Several lines of evidence suggest that both IRAK4 and IMiD activity contribute to the overall superior activity of the dual degraders. Proteomic analysis demonstrates degradation of both both IRAK4 and key IMiD substrates, including Ikaros and Ailolos. This activity results in an enhanced Type 1 IFN response signature compared to selective IRAK4 degraders or IMiD alone, suggesting cooperative biological activity. Degradation of both IRAK4 and IMiD substrates corelates with cell activity, consistent with a requirement for both activities to drive cell death. In xenograft models of MYD88 mutant DLBCL, daily oral dosing of lead dual - degraders demonstrates strong antitumor activity in xenograft models of MYD88 mutant lymphoma, including durable complete regressions that can be maintained for several weeks following cessation of dosing. Regressions are associated with degradation of both IRAK4 and IMiD substrates, consistent with the dual-targeting activity of these molecules. Collectively, these data support a strategy to combine IRAK4 degradation and IMiD activity in a single molecule that will have the potential benefits of enhanced therapeutic activity, increased convenience and decreased potential for drug combination challenges, such as DDI. Lead degraders based on this synergistic profile are being advanced towards IND in 2020.
Citation Format: Duncan H. Walker, Michele Mayo, Christine Klaus, Haojing Rong, Scott Rusin, Kirti Sharma, Alice McDonald, Veronica Campbell, Joseph Kelleher, Jared Gollob, Nello Mainolfi, Matt Weiss. Degraders targeting both IRAK4 and IMiD substrates show combinatorial effects leading to broader activity with durable and complete regressions in MYD88 mutant lymphoma xenografts in vivo [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 5222.