Abstract 5108: Potent small molecule compounds that selectively inhibit proliferation of ABC-DLBCL cell lines

Abstract

Abstract Diffuse large B cell lymphoma (DLBCL), which accounts for 25% of all lymphomas cases, has been classified into molecular subtypes including germinal center B cell like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal B cell lymphoma (PMBL). Among these subtypes, patients with ABC-DLBCLs have the worst prognosis because of the high chemo-resistance, and require effective therapies. Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 (MALT1) protease activity is linked to the pathogenesis of ABC-DLBCL. Therefore, a focused library of covalent compounds selected based on molecular docking on the reported crystal structure was screened for selective sensitivity to ABC-DLBCL, but not GCB-DLBCL cell lines. Optimization of initial hits resulted in the identification of lead compounds with an anti-proliferative EC50 of <100 nM selectively in ABC-DLBCL cell lines. Consistent with the previously reported role of MALT1 inhibitors, lead compounds also showed anti-proliferative activity in selected melanoma and NSCLC cell lines. The anti-proliferative activity of the lead compounds correlated well with the inhibition IL-6, a downstream marker of MALT1 signaling, in ABC-DLBCL cell line such as OCI-LY3. The lead compounds exhibited excellent drug-like properties including solubility, metabolic stability, lack of CYP inhibition, permeability and desired dose-dependent oral exposure in pharmacokinetic studies. In a repeated dose MTD study, the lead compounds showed good tolerability with an exposure multiple of >10 over cellular EC50 for up to 8 hours. The lead compounds showed dose-dependent tumor growth inhibition in a xenograft model upon oral dosing. In summary, we have identified novel and potent MALT1 inhibitors capable of selectively inhibiting proliferation of DLBCL cell lines with optimized drug-like properties including oral bioavailability. The data presented here strongly support further development of these compounds for DLBCL and other indications. Citation Format: Leena Khare Satyam, Dinesh Chikkanna, Vinayak Khairnar, Manoj Pothuganti, Sunil Panigrahi, Anirudha Lakshminarasimhan, Narasimha Rao, Wesley Balasubramanian, Sandeep Patil, Sreevalsam Gopinath, Gunta Upendra, Jwala Nagaraj, Kiran Aithal, Vijay Ahuja, Sanjeev Giri, Chetan Pandit, Murali Ramachandra. Potent small molecule compounds that selectively inhibit proliferation of ABC-DLBCL cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5108. doi:10.1158/1538-7445.AM2017-5108