Targeted Penetrating Motif Engineering of BH3 Mimetic: Harnessing Non-Canonical Amino Acids for Coinhibition of MCL-1 and BCL-xL in Acute Myeloid Leukemia.

ABSTRACT: Acute Myeloid Leukemia (AML) remains a formidable clinical challenge, predominantly due to the emergence of resistance to existing therapeutic regimens, including BCL-2 inhibitors like Venetoclax. Here, a novel approach is introduced by engineering BH3 mimetics utilizing non-canonical amino acids (ncAAs) to achieve dual inhibition of MCL-1 and BCL-xL. Through site saturation mutagenesis scanning, the I58(Chg) mutation is identified, significantly enhancing binding affinity with IC₅₀ values of 2.77 nm for MCL-1 and 10.69 nm for BCL-xL, reflecting an increase of fourfold or more. The developed vMIP-II-TAT-I peptide, incorporating a CXCR4-targeted penetrating motif, demonstrated superior cellular uptake, with mean fluorescence intensity (MFI) 7.2-fold higher in CXCR4-positive AML c

SUBMITTER: Wang Z 

PROVIDER: S-EPMC12279208 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature