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Design, synthesis, and biological evaluation of 2-morpholino-4H-chromen-4-one derivatives as a potent dual PI3K/BRD4

Krishnaiah Maddeboina1, Bharath Yada2, Cody C McHale2

  • 1Atrium Health Wake Forest Baptist Comprehensive Cancer Center/Levine Cancer Institute, Charlotte, NC, 28204, USA; Wake Forest University School of Medicine, Department of Biochemistry, Winston-Salem, NC, 27157, USA.

European Journal of Medicinal Chemistry
|May 21, 2026
PubMed

Insights

A novel dual inhibitor targeting PI3K and BRD4, LCI40, shows promise for cancer therapy. This compound effectively suppresses tumor growth and exhibits favorable pharmacokinetics with minimal toxicity, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Phosphoinositide 3-kinase (PI3K) inhibition offers limited therapeutic benefits and often results in drug resistance.
  • Combining PI3K and Bromodomain and Extra-Terminal Domain protein 4 (BRD4) inhibition demonstrates synergistic antitumor effects in MYC-driven cancers.

Purpose of the Study:

  • To design, synthesize, and evaluate novel dual PI3K/BRD4 inhibitors.
  • To identify a potent and selective dual inhibitor for potential cancer therapy.

Main Methods:

  • Synthesis of benzopyranone (BP)-based analogs.
  • Structure-activity relationship (SAR) analysis.
  • Enzymatic inhibition assays against PI3K and BRD4.
  • Kinase and bromodomain selectivity profiling.
  • In vitro and in vivo pharmacokinetic studies.
  • Evaluation in mantle cell lymphoma cell lines and mouse models.

Main Results:

  • LCI40 demonstrated significant enzymatic inhibitory activity against PI3K and BRD4.
  • LCI40 exhibited high selectivity across a panel of kinases and bromodomains.
  • Pharmacokinetic studies showed favorable in vitro and in vivo profiles.
  • LCI40 inhibited pAKT phosphorylation and suppressed c-MYC levels in Mino cells.
  • LCI40 displayed immunomodulatory effects with low toxicity to normal immune cells.

Conclusions:

  • LCI40 is a potent dual PI3K/BRD4 inhibitor with a promising selectivity profile.
  • LCI40 exhibits favorable pharmacokinetic properties and demonstrates antitumor activity.
  • LCI40 represents a promising lead candidate for developing novel cancer therapeutics.

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