BH3mimetika

BH3 mimetika, or BH3 mimetics, are a class of small-molecule compounds that imitate the action of BH3-only pro-apoptotic proteins. They bind to the hydrophobic BH3-binding grooves of anti-apoptotic BCL-2 family proteins, such as BCL-2, BCL-XL, BCL-W, MCL-1 and related factors, displacing pro-apoptotic effectors like BIM, BID, PUMA or NOXA. This release promotes mitochondrial outer membrane permeabilization, cytochrome c release, caspase activation and apoptotic cell death. The approach exploits the dependence of many cancers on anti-apoptotic BCL-2 proteins for survival.

Notable agents and development status. Venetoclax (ABT-199) is a selective BCL-2 inhibitor that has achieved clinical use in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) and in certain settings of acute myeloid leukemia (AML). ABT-263 (navitoclax) inhibits BCL-2 and BCL-XL but caused dose-limiting thrombocytopenia, guiding the development toward BCL-2 selective compounds. ABT-737 was an early lead compound that informed subsequent drug design. Inhibitors targeting MCL-1, such as S63845, AZD5991, and others including AMG 176 and BGB-11417, are in various stages of clinical trials, aimed at addressing resistance mediated by MCL-1 upregulation.

Clinical use and challenges. BH3 mimetics are often tested in combination with chemotherapy, hypomethylating agents, or other targeted therapies to enhance efficacy. Resistance can arise through upregulation of alternative anti-apoptotic proteins or mutations in Bax/Bak. Adverse effects include thrombocytopenia with BCL-XL inhibitors and tumor lysis syndrome with rapid BCL-2 inhibition, requiring careful patient selection and monitoring.