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Tumour cells often escape cell death by overexpressing anti\u2010apoptotic members of the BCL\u20102 protein family, particularly BCL\u20102, BCL\u2010xL, and MCL1. These proteins inhibit the intrinsic mitochondrial apoptotic pathway through intricate interactions with pro\u2010apoptotic partners and direct modulation of the mitochondrial outer membrane. Their pivotal role in cell survival has established them as attractive therapeutic targets. Over the past two decades, significant efforts have been devoted to developing selective small\u2010molecule inhibitors capable of neutralising these proteins and reactivating apoptosis. A first milestone was the discovery of ABT\u2010263 (navitoclax), a dual BCL\u20102\/BCL\u2010xL inhibitor. Building on this achievement, the development of venetoclax, a highly selective BCL\u20102 inhibitor, marked a major breakthrough, demonstrating potent pro\u2010apoptotic activity and clinical efficacy in several leukaemia subtypes. Despite these advances, the design of inhibitors of BCL\u20102 family members remains challenging, largely due to the structural characteristics of the BH3\u2010binding groove, which is both shallow and hydrophobic, complicating the identification of molecules with optimal binding affinity and selectivity. PROTACs targeting BCL\u2010xL may represent a promising future strategy, potentially overcoming the intrinsic limitations of small molecule inhibitors.<\/jats:p>","DOI":"10.1111\/jcmm.71036","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T07:10:06Z","timestamp":1775459406000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting\n                    <scp>BCL<\/scp>\n                    \u2010\n                    <scp>xL<\/scp>\n                    in Myeloid Malignancies: From Inhibitors to\n                    <scp>PROTAC<\/scp>"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-4791","authenticated-orcid":false,"given":"Daniela","family":"Cilloni","sequence":"first","affiliation":[{"name":"Department of Clinical and Biological Sciences University of Turin  Turin 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