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

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Leukemia, Myeloid, Acute*/drug therapy ; Leukemia, Myeloid, Acute*/metabolism ; Leukemia, Myeloid, Acute*/genetics ; bcl-X Protein*/metabolism ; bcl-X Protein*/genetics ; bcl-X Protein*/antagonists & inhibitors ; Myeloid Cell Leukemia Sequence 1 Protein*/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein*/genetics ; Myeloid Cell Leukemia Sequence 1 Protein*/antagonists & inhibitors ; Amino Acids*/metabolism; Humans ; Animals ; Mice ; Cell Line, Tumor ; Sulfonamides/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Antineoplastic Agents/pharmacology ; Xenograft Model Antitumor Assays ; Apoptosis/drug effects

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 IC 50 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 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-target effects, while laying the foundation for developing advanced BH3 mimetics with enhanced targeting, binding affinity, and efficacy for AML treatment.
(© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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FTWS2022018 Futian Healthcare Research Project; FTWS2023075 Futian Healthcare Research Project; 2023A1515012958 Guangdong Basic and Applied Basic Research Foundation; 2025A1515011804 Guangdong Basic and Applied Basic Research Foundation; JCYJ20220530144401004 Shenzhen Science and Technology Program; 202206193000001 Shenzhen Science and Technology Program

Keywords: MCL‐1 & BCL‐xL inhibition; acute myeloid leukemia; drug resistance; non‐canonical amino acids; targeted penetrating peptides

0 (bcl-X Protein)
0 (Myeloid Cell Leukemia Sequence 1 Protein)
0 (Amino Acids)
0 (Sulfonamides)
N54AIC43PW (venetoclax)
0 (MCL1 protein, human)
0 (Bridged Bicyclo Compounds, Heterocyclic)
0 (Antineoplastic Agents)
0 (BCL2L1 protein, human)

Date Created: 20250430 Date Completed: 20250717 Latest Revision: 20250723

20250723

PMC12279208

10.1002/advs.202503682

40305693