Discovery of a "First-in-Class" Selective Multikinase (CDK4/6/9-AURKA/B) Inhibitor, LCI133, for Neuroblastoma

  • J Med Chem. 2025 Nov 27;68(22):24024-24046. doi: 10.1021/acs.jmedchem.5c01688.
Krishnaiah Maddeboina  1  2 ,  Dhananjaya Pal  1 ,  Bharath Yada  1 ,  Cody C McHale  1 ,  Sandeep K Singh  3  4 ,  Yashpal S Chhonker  3  4 ,  Hailey L Dryden  1 ,  Ritchie Delara  5 ,  Vaidehi Mujumdar  5 ,  Qi Zhang  5 ,  Daryl J Murry  3  4 ,  Donald L Durden  1  2
Affiliations
  • 1. Atrium Health Wake Forest Baptist Comprehensive Cancer Center/Levine Cancer Institute, Charlotte, North Carolina 28204, United States.
  • 2. Wake Forest University School of Medicine, Department of Biochemistry, Winston-Salem, North Carolina 27157, United States.
  • 3. Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68106, United States.
  • 4. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68106, United States.
  • 5. Division of Gynecologic Oncology, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina 28204, United States.
PMID: 41198570 DOI: 10.1021/acs.jmedchem.5c01688
Abstract

Our central hypothesis in this report is that the development of a single small molecule inhibitor that binds to multiple targets will be safer and more efficacious against high-risk cancers which rapidly develop resistance to one targeted therapeutic agent. We used a rational pharmacophore merging strategy and X-ray crystal structures of CDK6, CDK9, and AURKA to discover LCI133, a "first-in-class" nanomolar (nM) potent CDK4/6/9-AURKA/B inhibitor. Selectivity profiling of LCI133 using the scanMAX kinome assay of 468 kinases revealed that it is highly selective for CDK4/9 and AURKA targets. Pharmacokinetic studies with LCI133-HCl in mice demonstrate a high systemic exposure (AUC) of 7812 ng × h/mL and maximum plasma concentration (Cmax) of 3305 ng/mL. Neuroblastoma (NB) cells displayed nM sensitivity to LCI133 in vitro, and we observed potent antitumor effects in vivo in a BE(2)-C neuroblastoma xenograft model, without overt toxicity and an increase in the overall survival rate.

Products