Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma

Wong, Kam Yuet; Chim, Chor Sang

doi:10.1111/jphp.13240

Cited by 17 publications

(10 citation statements)

References 31 publications

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“…68,70 Such combinations produce similar results in multiple myeloma and are more effective against cell lines such as U266 that are resistant to MCL1 or BCL2 inhibition alone. [76][77][78][79][80] However, targeting multiple anti-apoptotic proteins simultaneously increases the risk of inducing apoptosis in normal cells, particularly lymphocytes, and must be approached cautiously. The bone marrow microenvironment is likely to play a role in response to MCL1 inhibitors as well.…”

Section: Mcl1 Inhibitorsmentioning

confidence: 99%

BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

Gupta¹,

Ackley²,

Kaufman³

et al. 2021

BLCTT

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Although much progress has been made in the treatment of multiple myeloma, the majority of patients fail to be cured and require numerous lines of therapy. Inhibitors of the BCL2 family represent an exciting new class of drugs with a novel mechanism of action that are likely to have activity as single agents and in combination with existing myeloma therapies. The BCL2 proteins are oncogenes that promote cell survival and are frequently upregulated in multiple myeloma, making them attractive targets. Venetoclax, a BCL2 specific inhibitor, is furthest along in development and has shown promising results in a subset of myeloma characterized by the t(11;14) translocation. Combining venetoclax with proteasome inhibitors and monoclonal antibodies has improved responses in a broader group of patients, but has come at the expense of a toxicity safety signal that requires additional follow-up. MCL1 inhibitors are likely to be effective in a broader range of patients and are currently in early clinical trials. This review will cover much of what is known about the biology of these drugs, biomarkers that predict response, mechanisms of resistance, and unanswered questions as they pertain to multiple myeloma.

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Section: Mcl1 Inhibitorsmentioning

confidence: 99%

BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

Gupta¹,

Ackley²,

Kaufman³

et al. 2021

BLCTT

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“…Doxorubicin‐loaded alginate DDVs with surface functionalization showed promise in their targeted delivery to liver cancer . Alginate‐based particles have shown versatility in a diverse range of therapeutic applications, such as oral drug administration, controlled gastrointestinal release for optimal drug absorption, and as drug excipients …”

Section: Ddv Selectionmentioning

confidence: 99%

Advances in Receptor‐Mediated, Tumor‐Targeted Drug Delivery

Large

Soucy

Hebert

et al. 2018

Advanced Therapeutics

141

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Receptor-mediated drug delivery presents an opportunity to enhance therapeutic efficiency by accumulating drug within the tissue of interest and reducing undesired, off-target effects. In cancer, receptor overexpression is a platform for binding and inhibiting pathways that shape biodistribution, toxicity, cell binding and uptake, and therapeutic function. This review will identify tumor-targeted drug delivery vehicles and receptors that show promise for clinical translation based on quantitative in vitro and in vivo data. The authors describe the rationale to engineer a targeted drug delivery vehicle based on the ligand, chemical conjugation method, and type of drug delivery vehicle. Recent advances in multivalent targeting and ligand organization on tumor accumulation are discussed. Revolutionizing receptor-mediated drug delivery may be leveraged in the therapeutic delivery of chemotherapy, gene editing tools, and epigenetic drugs.in the site of interest. This is clinically important as reaching a therapeutic dosage locally and reducing systemic toxicity can be life-threatening or life-saving events for cancer patients.The design of targeted DDVs can be optimized by altering the size, shape, material, ligand, and ligand orientation. For systemic delivery, spherical DDVs less than 200 nm in diameter are standard, which is balanced by the trade off between surface area and volume ratio. DDVs are prepared from biomaterials based on the size, hydrophobicity, and ideal release of the drug. There are a diverse range of ligand candidates for DDV functionalization, including monoclonal antibodies (mAbs), peptides, oligosaccharides, small molecules, and aptamers. [5] These ligands can be tethered to vehicles or conjugated directly to drugs by covalent (typically thiol or amide-based reactions, or "click" chemistry) or noncovalent attachment; the type of reaction is often based on the material of the DDV. [6] Multi-targeted and patterned DDVs improved cancer cell binding and the overall therapeutic benefit in vivo. The ideal DDV platform may be rationally designed by evaluating the drug, release mechanism, mode of delivery into the body, and target cells.Utilizing these approaches, targeted DDVs were successfully translated from the research setting into clinical use, or are currently in preclinical trials. [7] Liposomal based DDVs were approved for use in cancer therapy, treating fungal diseases, analgesics, photodynamic therapy, and viral vaccines. [8] Specifically, FDA approved liposomal drug formulations, such as Mepact, Maribo, and Epaxal were proven to be effective for the treatment of nonmetastatic osteosarcoma, acute lymphoblastic leukemia, and hepatitis A, respectively. [9] Many targeted DDVs in clinical use are utilized for the treatment of multiple cancer types, as there is often broad overlap in malignant receptor overexpression across various carcinogenic tissues (Figure 1). The widely successful drug Pembrolizumab (Keytruda), a humanized IgG4 isotype mAb that targets the programmed cell death (PD-1) rec...

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“…Furthermore, in vitro studies illustrated that the triple therapy is a stronger synergism than the S63845 plus Venetoclax in resistant MM cell line (MM.1S) ( Algarín et al, 2020 ). In addition, the combination of S63845 and Venetoclax, enhanced the Venetoclax sensitivity and overcome resistance to Venetoclax in human myeloma cell lines (HMCLs) ( Wong and Chim, 2020 ).…”

Section: Development Of Selective Mcl-1 Inhibitorsmentioning

confidence: 99%

Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma

et al. 2021

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Multiple myeloma (MM) is a plasma cells neoplasm. The overexpression of Bcl-2 family proteins, particularly myeloid cell leukemia 1 (Mcl-1), plays a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis of MM. Thus, inhibition of the Mcl-1 protein considered as a therapeutic strategy to kill the myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. This review presents the critical role of Mcl-1 in the progression of MM, the most prominent BH3 mimetic and semi-BH3 mimetic that selectively inhibit Mcl-1, and could be used as single agent or combined with existing therapies.

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Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma

Cited by 17 publications

References 31 publications

BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma

Advances in Receptor‐Mediated, Tumor‐Targeted Drug Delivery

Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma

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