Jae H. Chang

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.

Figure S4 shows brain penetrance and intracranial efficacy in preclinical models

Table S4 shows the mutational landscape of EGFR mutant PDX models

Figure S5 shows pharmacodynamic effect of enozertinib on EGFR Protein

Supplementary Data 2 shows the variant allele frequency (VAF) of patient

Supplementary Data 1 sows GENIEv15.1 EGFR mutation analysis

EGFR mutations are common oncogenic drivers in non–small cell lung cancer (NSCLC), and approximately half of patients develop brain metastases over the course of their disease. Patients with nonclassic EGFR mutations, such as insertions in exon 20, are a high unmet need with a worse prognosis compared with patients with classic EGFR mutations. Here, we describe the discovery and development of enozertinib (formerly ORIC-114), a highly brain-penetrant, orally bioavailable, irreversible inhibitor that targets EGFR exon 20 mutations with unparalleled kinome selectivity. Preclinical studies revealed strong potency and tumor regressions driven by enozertinib across a broad range of atypical EGFR-mutant models. In a phase I clinical trial of enozertinib in patients with advanced NSCLC bearing atypical mutations in EGFR, a patient harboring an EGFR exon 20 insertion experienced sustained complete response of all systemic and brain metastases. Together, these findings identify enozertinib as a promising investigational inhibitor to address the unmet need for brain-penetrant therapies in NSCLC with EGFR exon 20 insertions or other atypical mutations.Significance:Preclinical and initial phase I clinical data demonstrate the potency, kinome selectivity, efficacy, and brain penetration of enozertinib in NSCLC with EGFR exon 20 insertions and atypical mutations, warranting further clinical development.

Figure S3 shows EGFR WT-sparing ratios in cellular assays

Table S2 shows the biochemical potency of enozertinib and other EGFR inhibitors across mutant EGFR proteins