Oncology Pipeline

B-cell lymphoma 2 (BCL-2) protein is the namesake member of the apoptosis-regulating BCL-2 family. BCL-2 family proteins are key regulators of apoptosis, which is vital for proper tissue development and cellular homeostasis.^1-3 Apoptosis can occur via activation of two different pathways: the extrinsic pathway, triggered by a death ligand binding to a death receptor, such as TNF-α to TNFR1³; and the intrinsic pathway, regulated by BCL-2 family proteins and their complex protein-protein interactions.^1,2 BCL-2 family proteins are functionally classified as either antiapoptotic, such as BCL-2, BCL-xL, and MCL-1, or proapoptotic, including BID, BIM, BAD, BAK, and BAX.^1-3

Antiapoptotic BCL-2 family members are often found to be variably upregulated in many types of human cancers, such as different subtypes of B-cell lymphoma and solid tumors, and are frequently correlated with decreased susceptibility to chemotherapeutics and increased radioresistance.¹ Overexpression of BCL-2 proteins may be an independent indicator of poor prognosis in malignancies including B-cell lymphomas and some solid tumors.¹

LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL-2, developed to avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition while also maintaining selectivity over MCL-1. In preclinical studies, LOXO-338 selectively inhibited BCL-2 dependent cell lines with limited toxicities in vivo.