A‑1210477, a selective MCL‑1 inhibitor, overcomes ABT‑737 resistance in AML

Wang, Qing; Hao, Siguo

doi:10.3892/ol.2019.10891

Cited by 12 publications

(12 citation statements)

References 39 publications

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“…Early MCL-1 inhibitors lacked specificity, however NMR-based screening, as with other BH3 mimetics, identified a large hydrophobic pocket in the P2 region of the protein that enabled more selective inhibitors to be designed [ 17 ]. Multiple approaches have identified small molecules with high affinity binding to MCL-1 and potent activity against MCL-1-dependent cells [ 17 , 53 , 54 , 55 , 56 , 57 ]. S63845, an early specific inhibitor of MCL-1, bound to its BH3 domain and inactivated the anti-apoptotic function of MCL-1 (K D = 0.19 nM)[ 58 , 59 ].…”

Section: Therapeutic Strategies For Promoting Apoptosis Directly—intrinsic Pathwaymentioning

confidence: 99%

Therapeutics Targeting the Core Apoptotic Machinery

Hamilton

Fox

Longley

et al. 2021

Cancers

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Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically “addicted” to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics.

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Section: Therapeutic Strategies For Promoting Apoptosis Directly—intrinsic Pathwaymentioning

confidence: 99%

Therapeutics Targeting the Core Apoptotic Machinery

Hamilton

Fox

Longley

et al. 2021

Cancers

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“…A-1210477 overcomes the resistance of AML mouse models and cell lines to the BCL-2/BCL-XL inhibitor agent (ABT-737) [ 123 ]. VU661013-resistant AML cells were significantly more sensitive to venetoclax than their initial response and that cells resistant to venetoclax were more sensitive to MCL-1 inhibitors [ 124 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting MCL-1 in cancer: current status and perspectives

et al. 2021

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Myeloid leukemia 1 (MCL-1) is an antiapoptotic protein of the BCL-2 family that prevents apoptosis by binding to the pro-apoptotic BCL-2 proteins. Overexpression of MCL-1 is frequently observed in many tumor types and is closely associated with tumorigenesis, poor prognosis and drug resistance. The central role of MCL-1 in regulating the mitochondrial apoptotic pathway makes it an attractive target for cancer therapy. Significant progress has been made with regard to MCL-1 inhibitors, some of which have entered clinical trials. Here, we discuss the mechanism by which MCL-1 regulates cancer cell apoptosis and review the progress related to MCL-1 small molecule inhibitors and their role in cancer therapy.

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“…As a control, we used a potent hMcl-1 binding ligand A1210477 (Figure A). Using our previously developed DELFIA displacement assay, we could verify that the agent is effective in displacing a biotinylated BH3 peptide from hMcl-1 with an IC 50 value of 14 nM that agrees with the reported affinity for this agent (Figure B) . Exposing the ligand to hMcl-1 causes perturbation in its aliphatic region of the 1D 1 H NMR spectrum, where several binding site residue resonances occur (Figure C,D), suggesting that the assay could be used to effectively identify hMcl-1 binding agents.…”

Section: Resultsmentioning

confidence: 99%

Mixture-Based Screening of Focused Combinatorial Libraries by NMR: Application to the Antiapoptotic Protein hMcl-1

et al. 2023

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We report on an innovative ligand discovery strategy based on protein NMR-based screening of a combinatorial library of ∼125,000 compounds that was arranged in 96 distinct mixtures. Using sensitive solution protein NMR spectroscopy and chemical perturbation-based screening followed by an iterative synthesis, deconvolutions, and optimization strategy, we demonstrate that the approach could be useful in the identification of initial binding molecules for difficult drug targets, such as those involved in protein−protein interactions. As an application, we will report novel agents targeting the Bcl-2 family protein hMcl-1. The approach is of general applicability and could be deployed as an effective screening strategy for de novo identification of ligands, particularly when tackling targets involved in protein−protein interactions.

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A‑1210477, a selective MCL‑1 inhibitor, overcomes ABT‑737 resistance in AML

Cited by 12 publications

References 39 publications

Therapeutics Targeting the Core Apoptotic Machinery

Therapeutics Targeting the Core Apoptotic Machinery

Targeting MCL-1 in cancer: current status and perspectives

Mixture-Based Screening of Focused Combinatorial Libraries by NMR: Application to the Antiapoptotic Protein hMcl-1

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