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

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number2
JournalMolecular Biomedicine
Volume3
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • BRD4
  • Bromodomain
  • Bruton's tyrosine kinase
  • Inhibitor
  • Mantle cell lymphoma
  • Phosphatidylinositol-3 kinase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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