TargetingALKRearrangements

Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

“…Unless otherwise indicated, all reagents and solvents were obtained from commercial sources and used as received. 1 H and 13 C NMRs were obtained on a Bruker Avance at 400 and 101 MHz, respectively, in the solvent indicated with tetramethylsilane as an internal standard. Analytical HPLC was run using a Zorbax RX-C8, 5 mm × 150 mm column, eluting with a mixture of acetonitrile and water containing 0.1% trifluoroacetic acid with a gradient of 10−100% over 5 or 20 min, wavelength of 254 and 290 nm to assess purity of final targets.…”

“…The biological rationale, therapeutic intervention, and clinical proof of concept data with small–molecule ALK inhibitors have been well documented. − Current approaches toward ALK+ cancers have focused on improving potency toward drug-induced activating mutations as well as incorporation of ancillary activity against other oncogenic signaling mechanisms , to combat resistance and the recurrence of local disease and distal metastases. Our initial efforts in the ALK field led to the discovery of 1 (Figure ), a selective ALK inhibitor which advanced to preclinical development. , Several distinct challenges for our next generation of inhibitors were readily apparent which included not only addressing the limitations of the lead molecule itself (e.g., metabolic stability, high plasma protein binding) but the broader, changing landscape of the small-molecule ALK inhibitor field, which has seen the approval of three distinct molecular entities to treat EML4-ALK defined NSCLC as first or second line therapy, as well as specific drug-induced resistance.…”