AP26113 as inhibitor of cancer biomarkers

AP26113, or Brigatinib, is a novel, synthetic, orally active and potent small-molecule inhibitor of anaplastic lymphoma kinase (ALK). ALK is a receptor tyrosine kinase of the insulin receptor family, which was originally identified as a part of the fusion protein NPM−ALK resulting from a reciprocal translocation between chromosomes 2 and 5 in anaplastic large-cell lymphomas (ALCL). ALK plays an important role in nervous system development and ALK dysregulation and gene rearrangements are associated with a series of tumors. The half maximal inhibitory concentration IC50 for ALK ranges from 5 nmol/l to 11 nmol/l.

AP26113 induced tumor regression in BaF3 xenograft model expressing EML4-ALK, and EML4-ALK harboring G1269S and L1196M (gatekeeper) mutations. In preclinical studies, AP26113 was shown to be active against all 9 clinically-identified crizotinib-resistant mutants tested. AP26113 is also a potent, reversible inhibitor of activated and T790M-mutant EGFR, yet it does not inhibit the native enzyme. A phase I/II study was initiated (NCT01449461) to evaluate AP26113 as a dual ALK/mutant EGFR inhibitor (2013). In the dose escalation phase (30-300 mg), two dose limiting toxicities were observed, grade 3 ALT elevations at 240 mg and grade 4 dyspnea at 300 mg. The recommended phase II dose was identified as 180 mg. AP26113 has promising anti-tumor activity in pts with crizotinib-resistant ALK+ NSCLC, including pts with brain metastases. The most common adverse effects were nausea (45%), fatigue (39%), diarrhea (27%).

AP26113 is also capable of inhibiting the ALK tyrosine kinase gatekeeper mutation L1196M (IC50: 15 nmol/l to 45 nmol/L), mutant epidermal growth factor receptor (EGFR) containing the gatekeeper T790M mutation and c-ros oncogene 1 (ROS1) by disrupting their signaling pathways and eventually inhibits tumor cell growth in susceptible tumor cells. EGFR is overexpressed in a variety of cancer cell types. Moreover, AP26113 has been found to be active against H3122 cells (both sensitive and resistant) and Ba/F3 cells harboring native or mutant EML4-ALK (IC50: 10 nM and 24 nM respectively).

References

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