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

  • Eur J Med Chem. 2026 Oct 5:315:118944. doi: 10.1016/j.ejmech.2026.118944.
Krishnaiah Maddeboina  1 ,  Bharath Yada  2 ,  Cody C McHale  2 ,  Dhananjaya Pal  2 ,  Sandeep K Singh  3 ,  Yashpal S Chhonker  3 ,  Daryl J Murry  4 ,  David R Soto-Pantoja  5 ,  Donald L Durden  6
Affiliations
  • 1. Atrium 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. Electronic address: [email protected].
  • 2. Atrium Health Wake Forest Baptist Comprehensive Cancer Center/Levine Cancer Institute, Charlotte, NC, 28204, USA.
  • 3. Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA.
  • 4. Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68106, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68106, USA.
  • 5. Wake Forest University School of Medicine, Department of Cancer Biology, Winston-Salem, NC, 27157, USA.
  • 6. Atrium 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. Electronic address: [email protected].
PMID: 42166816 DOI: 10.1016/j.ejmech.2026.118944
Abstract

The inhibition of PI3K has only a limited therapeutic effect and often leads to drug resistance. Combining PI3K and BRD4 inhibition results in a beneficial antitumor effect in MYC-driven hematological malignancies and solid tumors, underlying the significance of developing dual kinase/epigenetic inhibitors. In this study, we report the design, synthesis, and biological evaluation of novel dual PI3K/BRD4 inhibitors. A series of benzopyranone (BP) based analogs were synthesized and subjected to structure activity relationship analysis (SAR). LCI40 displayed significant enzymatic inhibitory activity against PI3K, BRD4 proteins and demonstrated a remarkable selectivity profile against a 468 panel of kinases and 31 bromodomains. It exhibited favorable in vitro and in vivo pharmacokinetics in a mouse model. In a mantle cell lymphoma cell line (Mino), LCI40 inhibited the phosphorylation of pAKT (S473) and suppressed c-Myc levels. Further, LCI40 displayed immunomodulatory capacity with minimal toxicity to normal mouse immune cells. LCI40 is a promising lead candidate for development as a dual PI3K/BRD4 Inhibitor for Cancer therapy.

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