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Vann KR, Pal D, Smith AL, et al. Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma. Mol Biomed. 2022;3(1):2doi: 10.1186/s43556-021-00066-9.
Vann, K. R., Pal, D., Smith, A. L., Sahar, N. E., Krishnaiah, M., El-Gamal, D., & Kutateladze, T. G. (2022). Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma. Molecular biomedicine, 3(1), 2. https://doi.org/10.1186/s43556-021-00066-9
Vann, Kendra R, et al. "Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma." Molecular biomedicine vol. 3,1 (2022): 2. doi: https://doi.org/10.1186/s43556-021-00066-9
Vann KR, Pal D, Smith AL, Sahar NE, Krishnaiah M, El-Gamal D, Kutateladze TG. Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma. Mol Biomed. 2022 Jan 15;3(1):2. doi: 10.1186/s43556-021-00066-9. PMID: 35031886.
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Mol Biomed. 2022 Jan 15;3(1):2. doi: 10.1186/s43556-021-00066-9.

Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma.

Molecular biomedicine

Kendra R Vann, Dhananjaya Pal, Audrey L Smith, Namood-E Sahar, Maddeboina Krishnaiah, Dalia El-Gamal, Tatiana G Kutateladze

Affiliations

  1. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
  2. Molecular Targeted Therapeutics Laboratory, Levine Cancer Institute, Charlotte, NC, USA.
  3. Division of Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  4. Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
  5. Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA. [email protected].

PMID: 35031886 DOI: 10.1186/s43556-021-00066-9

Abstract

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin's lymphoma characterized by poor prognosis. The complexity of MCL pathogenesis arises from aberrant activities of diverse signaling pathways, including BTK, PI3K-AKT-mTOR and MYC-BRD4. Here, we report that MCL-related signaling pathways can be altered by a single small molecule inhibitor, SRX3305. Binding and kinase activities along with resonance changes in NMR experiments reveal that SRX3305 targets both bromodomains of BRD4 and is highly potent in inhibition of the PI3K isoforms α, γ and δ, as well as BTK and the drug-resistant BTK mutant. Preclinical investigations herein reveal that SRX3305 perturbs the cell cycle, promotes apoptosis in MCL cell lines and shows dose dependent anti-proliferative activity in both MCL and drug-resistant MCL cells. Our findings underscore the effectiveness of novel multi-action small molecule inhibitors for potential treatment of MCL.

© 2022. The Author(s).

Keywords: BRD4; Bromodomain; Bruton's tyrosine kinase; Inhibitor; Mantle cell lymphoma; Phosphatidylinositol-3 kinase

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