Lead Optimization of an Aminopyrazole Scaffold to EXEL-1855, a Highly Selective PLK4 Inhibitor with Potent Antitumor Efficacy
Abstract Polo-like kinase 4 (PLK4) is a serine/threonine kinase that has an essential role in regulating centriole duplication and centrosome biogenesis during cell-cycle progression and a potential therapeutic target in various human cancers. Structure-guided lead optimization of an aminopyrazole scaffold at three key vectors led to the identification of EXEL-1855, which demonstrated a significant improvement in cellular potency, increased selectivity over related-kinases and an improved pharmacokinetic profile. Targeting the non-conserved Met91 residue in the PLK4 lower hinge region and optimizing this interaction, enabled EXEL-1855 to be most selective PLK4 inhibitor reported to date. In a preclinical CHP-134 neuroblastoma mouse xenograft model, EXEL-1855 showed robust efficacy and was well-tolerated at all dose levels. Taken together, our medicinal chemistry campaign resulted in a highly optimized, orally bioavailable, and efficacious inhibitor of PLK4, with the potential to advance as an oral single-agent for the treatment of neuroblastoma with a projected human dose of 540 mg QD.
Authors
- Aditya Kumar (ORCID: https://orcid.org/0000-0001-9580-8245)
- Jae Hoon Chang (ORCID: https://orcid.org/0000-0003-3457-7695)
- Dana M. Gwinn (ORCID: https://orcid.org/0009-0003-8650-0224)
- Trevor Chang
- Brian Sherer
- André H. St. Amant (ORCID: https://orcid.org/0000-0002-4842-1918)
- Jeremy M. Murray (ORCID: https://orcid.org/0000-0002-2161-9326)
- Sanjay Bhattarai (ORCID: https://orcid.org/0009-0006-1930-7928)
- Ryan L. Gonciarz (ORCID: https://orcid.org/0000-0002-6600-7032)
- Justin M. Salvant (ORCID: https://orcid.org/0000-0001-8359-8105)
- Leo Mok
- John M. Sanders (ORCID: https://orcid.org/0000-0002-3788-4220)
- Jo-Ting Chang (ORCID: https://orcid.org/0009-0004-4993-862X)
- Nigam M. Mishra (ORCID: https://orcid.org/0000-0003-2695-6695)
- Deepak Gurbani (ORCID: https://orcid.org/0000-0002-0982-7173)
- Heather J. Finlay (ORCID: https://orcid.org/0000-0003-2309-0136)
- Nina M. Muñoz (ORCID: https://orcid.org/0000-0001-7733-4883)
- Huy H. Nguyen (ORCID: https://orcid.org/0000-0001-9167-7460)
- Wei Xu (ORCID: https://orcid.org/0000-0002-7834-0086)
- Joon Won Jeong (ORCID: https://orcid.org/0009-0009-1138-6870)
- Ziqiang Wang (ORCID: https://orcid.org/0009-0003-5268-2170)
- Faming Jiang
- Halesha Basavarajappa
- Christopher Kochansky
- David Cole
- Danny Ng
Institutions
- Exelixis (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-09-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c01844
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00