The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that plays a key role in the development of different tumor types. Even though the oncogenic protein NPM-ALK was originally identified as responsible for a subset of Anaplastic Large Cell Lymphoma (ALCL), its tumorigenic role in subsets of Non-Small Cell Lung Cancer (NSCLC) have been reported to be dependent on activated forms of ALK, the most frequent being the EML4-ALK protein. Later on other oncogenic forms of the strictly related c-ros Oncogene 1 kinase (ROS1) and tropomyosin receptor kinase A (TRKA) have been found to be crucial in the same tumor indication. In addition TRKs fusion proteins have been also identified in subsets of colorectal carcinoma (CRC) and in other tumor types. Despite the remarkable clinical activity of the ALK inhibitor Crizotinib, the emergence of resistance mutations and of brain metastasis often cause patient relapse. The high-throughput screening (HTS) of our corporate compound collection allowed us to identify a 3-aminoindazole derivative endowed with good biochemical potency against ALK (IC50 = 0.073 μM) and good antiproliferative activity on the ALK-dependent ALCL Karpas-299 cell line (IC50 = 0.253 μM). From this starting point a medicinal chemistry effort led to the final candidate compound Entrectinib, that potently inhibits the ALK kinase (IC50 = 12 nM), and the proliferation of the ALK-dependent Karpas-299 cell line (IC50 = 31 nM). Entrectinib is characterized by good oral bioavailability in all animal species, excellent in vivo efficacy in ALK-driven tumor models, efficient penetration of the blood-brain barrier (BBB) and good antiproliferative activity on Ba/F3 cell line transfected with different mutated forms of EML4-ALK. Moreover it is a potent inhibitor of the closely related tyrosine kinases ROS1 (IC50 = 7 nM) and TRKs (IC50 = 1 – 5 nM), and is highly efficacious in in vivo related tumor models. Patients’ treatment with Entrectinib resulted in clinically meaningful, deep and durable systemic responses (data recently presented in 19th World Conference on Lung Cancer WCLC 2018 and in the European Society for Medical Oncology Congress ESMO 2018). The molecule is currently undergoing registration enabling Phase II Clinical Trials for the treatment of selected patients affected by ALK, ROS1-, and TRK-positive tumors.

Discovery of entrectinib: A novel and potent inhibitor of ALK, ROS1, and Pan-TRKs kinases active in multiple molecularly defined cancer indications

2019 Spring National Meeting

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