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Chronic activation of Bruton’s Tyrosine Kinase (BTK) signaling is a hallmark of B cell malignancies. Over the last decade, covalent and reversible inhibitors of BTK have proven effective for the treatment of many of these including chronic lymphocytic leukemia, diffuse large B cell lymphoma, mantle cell lymphoma, marginal zone lymphoma and Waldenstrom macroglobulinemia. However, the long-term efficacy of BTK inhibitors has been limited by both tolerability and the emergence of acquired resistance mutations. Mutations at C481, for example, dramatically reduce the binding of covalent BTK inhibitors, whereas other clinically-observed mutations such as V416L, T474I, and L528W reduce or eliminate the activity of next-generation non-covalent inhibitors. Targeted protein degradation is emerging as a new modality of small molecule drug discovery that offers improved selectivity and the potential to overcome resistance mutations through its ability to efficiently remove therapeutically relevant proteins such as BTK from cells. This approach has the further benefit of eliminating the scaffolding function of proteins that are otherwise unaffected by enzymatic inhibitors. Here, we present the discovery, structure-activity relationships, and pre-clinical characterization of NX-2127, a targeted protein degrader of BTK with concomitant immunomodulatory activity (IKZF1/3 degradation). NX-2127 degrades BTK in multiple B cell lymphoma lines with DC50’s in the range of 1-13 nM. NX-2127 displays efficient cellular degradation yet binds to WT and mutant BTK with affinities that render covalent and noncovalent BTK inhibitors ineffective, illustrating the power of event-driven pharmacology. NX-2127 drives cellular ternary complex formation between BTK and CRBN by inducing positive cooperativity in both WT and acquired resistance mutant settings. Consequently, NX-2127 induces potent degradation of C481S, T474I, V416L, and L528W-mutant BTK and suppresses activation marker expression on cells harboring these mutations. Furthermore, NX-2127 demonstrates oral bioavailability across pre-clinical species and shows robust tumor growth inhibition in WT and mutant mouse models of lymphoma upon once daily PO dosing. In pre-clinical safety studies, NX-2127 demonstrates an acceptable safety profile. NX-2127 is currently in phase 1 clinical trials (NCT04830137) for hematological malignancies. Citation Format: Jeffrey T. Mihalic, Nivetha Brathaban, Brandon Bravo, Timothy Ingallinera, Daisuke Kato, Hao Lu, Jun Ma, Joel McIntosh, Austin Tenn-McClellan, Ratul Mukerji, Mark A. Noviski, Ge Peng, Luz Perez, Ryan Rountree, May Tan, Jeffrey Wu, Jordan Ye, Stephanie Yung. NX-2127: A first-in-class clinical stage degrader of BTK and IKZF1/3 for the treatment of patients with B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3423. |
