2. Academic Validation
  3. Discovery of N-(3-fluorophenyl)-2-(4-((7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-yl)amino)phenyl)acetamide as the first orally active selective aurora kinase B inhibitor

Discovery of N-(3-fluorophenyl)-2-(4-((7-(1-methyl-1H-pyrazol-4-yl)quinazolin-4-yl)amino)phenyl)acetamide as the first orally active selective aurora kinase B inhibitor

  • Eur J Med Chem. 2025 Sep 15:294:117735. doi: 10.1016/j.ejmech.2025.117735.
Phuc Tran 1,  Marialuisa Moccia 2,  Xiuqi Wang 1,  Annalisa Brescia 2,  Giorgia Federico 2,  Naresh Gunaganti 1,  Zhengyu Wang 3,  Min Yang 4,  Minmin Wang 4,  Baha'a Jabali 1,  Wei Yan 3,  Brendan Frett 1,  Massimo Santoro 2,  Francesca Carlomagno 5,  Hong-Yu Li 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Napoli, Italy.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pharmacology, The Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
  • 4 Department of Pharmacology, The Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
  • 5 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Napoli, Italy. Electronic address: francesca.carlomagno@unina.it.
  • 6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Pharmacology, The Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. Electronic address: lih1@uthscsa.edu.
PMID: 40398151 DOI: 10.1016/j.ejmech.2025.117735
Abstract

Cell cycle deregulation is a crucial hallmark of tumorigenesis, leading to uncontrolled cell growth. Overexpression of serine/threonine Aurora Kinase B (AURKB) is a common feature of human Cancer, particularly of the most aggressive subtypes, and it contributes to the alteration of the cell cycle. Thus, AURKB is considered a promising target for Cancer treatment; however, no AURKB pharmacological inhibitor has been approved so far. We previously reported SP-96, a quinazoline non-ATP competitive AURKB inhibitor, which exhibited sub nanomolar activity in enzymatic assay. However, SP-96 cellular activity was hampered by its poor cellular activities. Herein, we designed and synthesized a new series of quinazoline derivatives featuring improved membrane penetration. Compound 4b demonstrated efficacy in human cancer-derived cells and was orally active at low dose in a mouse xenograft model and correlated with the drug concentration in plasma. Importantly, a closely related compound 7o attached with solubilizing group is orally bioavailable in rats. In conclusion, compounds 4b and 7o represents a promising lead series for further optimization to develop an oral clinical AURKB inhibitor candidate.

Keywords

Aurora kinase B; Kinase inhibitors; Orally active; Selectivity; Structure activity relationship (SAR); Xenograft.

Figures
Products