TW-37: A Comprehensive Preclinical Assessment of a Dual Bcl-2/Mcl-1 Inhibitor

Executive Summary

TW-37 is a potent, nonpeptidic, small-molecule inhibitor of the B-cell lymphoma-2 (Bcl-2) family of anti-apoptotic proteins, developed through a rational, structure-based design strategy. As a dual inhibitor, it demonstrates high affinity for both Myeloid cell leukemia-1 (Mcl-1) and Bcl-2, with a lower but notable affinity for B-cell lymphoma-extra large (Bcl-xL). This profile positions it as a potential tool to address the intrinsic survival mechanisms that drive tumorigenesis and confer resistance to conventional therapies. An extensive body of preclinical research has documented its promising biological activity. Both in vitro and in vivo studies have consistently demonstrated its pro-apoptotic, anti-proliferative, and antiangiogenic effects across a broad spectrum of hematological and solid tumor models, including lymphoma, pancreatic cancer, head and neck cancer, and neuroblastoma. Furthermore, TW-37 has shown significant synergistic potential, enhancing the cytotoxic effects of standard chemotherapeutic regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and cisplatin.