37OCSummary for 37OC
| Entry DOI | 10.2210/pdb37oc/pdb |
| Related | 37OB |
| Descriptor | Serine/threonine-protein kinase PLK4, PHOSPHATE ION, (7R)-N-{3-[1-(2-fluoro-2-methylpropyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]-1H-pyrazol-4-yl}-7-hydroxy-7-(trifluoromethyl)-4-azaspiro[2.5]octane-4-carboxamide, ... (4 entities in total) |
| Functional Keywords | plk4, kinase, inhibitor, sbdd, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 32314.11 |
| Authors | |
| Primary citation | Gonciarz, R.L.,Chang, T.,St Amant, A.H.,Jeong, J.W.,Ng, D.,Mishra, N.M.,Bhattarai, S.,Salvant, J.M.,Chang, J.T.,Jiang, F.,Basavarajappa, H.,Wang, Z.,Cole, D.,Nguyen, H.H.,Chang, J.H.,Kumar, A.,Mok, L.,Xu, W.,Sanders, J.M.,Gurbani, D.,Gwinn, D.M.,Sherer, B.A.,Munoz, N.M.,Kochansky, C.,Murray, J.M.,Finlay, H.J. Lead Optimization of an Aminopyrazole Scaffold to EXEL-1855, a Highly Selective PLK4 Inhibitor with Potent Antitumor Efficacy. J.Med.Chem., 69:22637-22656, 2026 Cited by PubMed 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. PubMed: 42917933DOI: 10.1021/acs.jmedchem.6c01844 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.69 Å) |
Structure validation
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