TAK-788

Mobocertinib is under investigation in clinical trial NCT04129502 (TAK-788 as First-line Treatment Versus Platinum-based Chemotherapy for Non-small Cell Lung Cancer (NSCLC) With EGFR Exon 20 Insertion Mutations).|Mobocertinib is an orally available inhibitor of human epidermal growth factor receptor (EGFR) exon 20 insertion mutations, with antineoplastic activity. Upon oral administration, mobocertinib, and its active metabolites, specifically and irreversibly binds to and inhibits exon 20 insertion mutations of EGFR. This prevents EGFR-mediated signaling and leads to cell death in tumor cells expressing exon 20 insertion mutations. In addition, mobocertinib may inhibit the activity of other EGFR family members, such as human epidermal growth factor receptor 2 (HER2; ERBB2) and HER4. EGFR, HER-2 and -4 are receptor tyrosine kinases often mutated in numerous tumor cell types. They play key roles in tumor cell proliferation and tumor vascularization.
Mobocertinib is derived from osimertinib, a second-generation TKI which exhibits only limited activity against several resistant EGFRex20ins mutants. Both inhibitors are structurally identical except that the pyrimidine ring of moboceritinib incorporates a snugly fitting isopropyl ester group that targets a previously unoccupied pocket, resulting in expanded coverage of EGFRex20ins mutations as well as improved selectivity over wildtype EGFR vs. osimertinib.
Class: receptor tyrosine kinaseTreatment: NSCLC with EGFR alterationsOral bioavailability = 37%Elimination half-life = 18 h