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Here, a novel approach is introduced by engineering BH3 mimetics utilizing non\u2010canonical amino acids (ncAAs) to achieve dual inhibition of MCL\u20101 and BCL\u2010xL. Through site saturation mutagenesis scanning, the I58(Chg) mutation is identified, significantly enhancing binding affinity with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 2.77 n\n                    <jats:sc>m<\/jats:sc>\n                    for MCL\u20101 and 10.69 n\n                    <jats:sc>m<\/jats:sc>\n                    for BCL\u2010xL, reflecting an increase of fourfold or more. The developed vMIP\u2010II\u2010TAT\u2010I peptide, incorporating a CXCR4\u2010targeted penetrating motif, demonstrated superior cellular uptake, with mean fluorescence intensity (MFI) 7.2\u2010fold higher in CXCR4\u2010positive AML cells and exhibited a high selectivity index (SI) for AML cells, with minimal impact on normal human hematopoietic stem cells (HSCs). When combined with Venetoclax, this peptide induced synergistic apoptosis, reducing tumor burden and prolonging survival in an AML mouse model, with median survival extended to 53 days from 37 days with Venetoclax alone. These findings reveal the therapeutic potential of dual inhibition in overcoming Venetoclax resistance and selectively targeting leukemic cells with reduced off\u2010target effects, while laying the foundation for developing advanced BH3 mimetics with enhanced targeting, binding affinity, and efficacy for AML treatment.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503682","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T19:52:16Z","timestamp":1746042736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeted Penetrating Motif Engineering of BH3 Mimetic: Harnessing Non\u2010Canonical Amino Acids for Coinhibition of MCL\u20101 and BCL\u2010xL in Acute Myeloid Leukemia"],"prefix":"10.1002","volume":"12","author":[{"given":"Zhe","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology The Eighth Affiliated Hospital Sun Yat\u2010sen 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