Aminopyrazole Lead Optimization Yields Selective PLK4 Inhibitor EXEL-1855
- Exelixis researchers optimized an aminopyrazole hit series targeting PLK4, a kinase essential for centriole duplication, culminating in the advanced compound EXEL-1855.
- Structure-guided SAR and selectivity profiling addressed off-target kinase liabilities that had limited earlier aminopyrazole PLK4 inhibitors such as centrinone.
- In preclinical tumor models, EXEL-1855 showed strong antitumor activity, supporting its selection as a development candidate.
💡 Points
Selectivity was always the aminopyrazole scaffold's weak spot — centrinone's off-target kinase hits (PLK1/2/3, Aurora) made it a great chemical probe but a poor drug candidate. Getting EXEL-1855 to "development candidate" with a clean kinome profile is the real milestone here, not the potency number. PLK4's centrosome-duplication mechanism is also refreshingly uncrowded real estate next to the CDK/Aurora pileup.