Abstract 2497: FCN-338, a novel and selective Bcl-2 inhibitor, exhibits potent anti-tumor activity in B-cell lymphoma
Authors: Lin Shu , Zhao Xingdong , Liu Hongbin , Zhang Huajie , Chen Zhifang , Jiang Lihua , Liu Yanxin , Lin Min , Rong Yue , Tan Rui , Zhou Zuwen , Zou Zongyao , Gao Yuwei , Wang Weibo 
Published: August 2019

B-cell lymphoma-2 (Bcl-2) family proteins are key regulators of apoptosis, which is vital for proper tissue development and cellular homeostasis. Apoptosis occurs via activation of two different pathways: the extrinsic pathway, triggered by a death ligand binding to a death receptor, such as TNF-α to TNFR1; and the intrinsic pathway, regulated by Bcl-2 family proteins and their complex protein-protein interactions. Bcl-2 family proteins are functionally classified as either anti-apoptotic, such as Bcl-2, Bcl-xL and Mcl-1, or pro-apoptotic, including Bid, Bim, Bad, Bak and Bax. Anti-apoptotic Bcl-2 family members are often found to be up-regulated in many types of human cancers, such as different subtypes of B-cell lymphoma and diverse solid tumors, and are frequently been correlated with decreased susceptibility to chemotherapeutics and to increased radio-resistance. Overexpression of Bcl-2 proteins is an independent indicator of poor prognosis in tumors including chronic lymphocytic leukemia (CLL), prostate cancer, and small cell lung cancer (SCLC). Therefore, targeting Bcl-2 and its pro-survival relatives that form the core anti-apoptotic machinery, has emerged as a promising therapeutic approach in cancer. To that end, we have developed a novel and selective Bcl-2 inhibitor, FCN-338, with nanomolar affinity to Bcl-2 and physicochemical properties suitable for oral administration. FCN-338 exhibits much greater affinity to Bcl-2 than Bcl-xL, suggesting its good potential to avoid thrombocytopenia caused by the inhibition of Bcl-xL. FCN-338 has shown remarkable anti-proliferation potency against a panel of Bcl-2-addicted human B-cell lymphoma cell lines, including DOHH2 follicular lymphoma (FL) cell line (IC50 2 nM), Mino diffuse large B-cell lymphoma (DLBCL) cell line (IC50 23 nM), and RS4;11 acute lymphoblastic leukemia (ALL) cell line (IC50 35 nM), but not in Bcl-xL-dependent H146 SCLC cell line (IC50 &gt;4,500 nM). Correspondingly, in vivo efficacy of FCN-338 was demonstrated in a variety of xenograft models derived from FL, DLBCL and ALL tumors. FCN-338 dramatically caused tumor regression in a dose-dependent manner. In the non-clinical studies, FCN-338 exhibits much improved pharmacokinetic properties with higher T1/2, dose-normalized AUC and bioavailability in dogs compared with the FDA-approved Bcl-2 inhibitor ABT-199. Preferable safety profiles of FCN-338 were shown with no potential hERG inhibitory effect and less drug-drug interaction potential, as evidenced by no inhibitory effect (IC50 &gt;50 μM) on CYP2C9 enzyme compared with ABT-199 (IC50 1.05 μM). Together, our findings highlight the therapeutic potential of FCN-338 to be used as effective therapy across a broad range of Bcl-2-addicted B-cell malignancies.

Citation Format: Shu Lin, Xingdong Zhao, Hongbin Liu, Huajie Zhang, Zhifang Chen, Lihua Jiang, Yanxin Liu, Min Lin, Yue Rong, Rui Tan, Zuwen Zhou, Zongyao Zou, Yuwei Gao, Weibo Wang. FCN-338, a novel and selective Bcl-2 inhibitor, exhibits potent anti-tumor activity in B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2497.