Targeting MCL-1 in cancer: current status and perspectives

Wang, Haolan; Guo, Ming; Wei, Hudie; Chen, Yongheng

doi:10.1186/s13045-021-01079-1

Cited by 167 publications

(144 citation statements)

References 150 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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“… 28 In addition to MCL-1, overexpression of BCL2A1, an antiapoptotic BCL-2 homolog, was significantly expressed in monocytes rendering acute monocytic leukemias (AML-M5) more resistant to VEN treatment. 29 – 31 Investigations of therapies targeting MCL-1 directly, by the addition of cytotoxic chemotherapy to downregulate MCL-1, or through targeting of alternative myeloid transcription programs in AML with monocytic differentiation using VEN in combination with bromodomain and extra-terminal domain inhibitors may prove to be effective strategies to mitigate resistance and relapse to VEN. 30 , 32 , 33 Several phase I investigations of MCL-1 inhibitors as monotherapy and in combination with venetoclax or other cytotoxic agents are currently ongoing (NCT03218683, NCT05107856, NCT03218683, and NCT03218683).…”

Section: Venetoclax Bcl-2 and The Intrinsic Apoptotic Pathwaymentioning

confidence: 99%

Advancing the standard: venetoclax combined with intensive induction and consolidation therapy for acute myeloid leukemia

Lachowiez

Atluri

DiNardo

2022

Therapeutic Advances in Hematology

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The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with lower-intensity therapy is an efficacious treatment for acute myeloid leukemia (AML). VEN in combination with the hypomethylating agent azacitidine improved rates of response and measurable residual disease (MRD)-negative remissions in addition to overall survival in the pivotal phase 3 VIALE-A trial compared with azacitidine monotherapy and has since emerged as the current standard of care in older or unfit patients with AML. In younger, fit patients with AML, intensive induction and consolidation chemotherapy (IC) is commonly employed as frontline therapy; however, relapse remains the principal cause of treatment failure in approximately 30–40% of patients. Improved IC regimens that increase MRD-negative response rates, result in durable remissions, and enable transition to curative allogeneic hematopoietic stem cell transplantation in appropriate patients remain an area of active inquiry. Preliminary results from trials investigating the combination of VEN with IC have reported promising findings to date, with composite complete remission and MRD-negative remission rates of approximately 89–94% and 82–93%, respectively, correlating with improved 12-month event-free and overall survival compared to historical outcomes with IC. Herein, we discuss ongoing trials investigating VEN in combination with IC in addition to outcomes within specific molecularly defined subgroups; review the molecular mechanisms of sensitivity and resistance to VEN, and highlight future combinations of VEN with novel targeted therapies for the treatment of AML.

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“…1 C and D and S1). Mcl-1 is an anti-apoptotic protein that, functionally like Bcl-2 and Bcl-X L , negatively regulates intrinsic apoptotic pathway [ 23 , 24 ]. We also checked Mcl-1 levels in these cell lines and found that APG-1252-M1-senstive cell lines tended to have lower levels of Mcl-1 than those insensitive to APG-1252-M1, showing a significant negative correlation between Mcl-1 abundance and cell response to APG-1252-M1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%