n-(3-fluoro-4-((1-methyl-6-(1h-pyrazol-4-yl)-1h-indazol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1-2-dihydropyridine-3-carboxamide and Neoplasms

Dysregulation of the AXL receptor tyrosine kinase has been associated with many types of cancer. It has not been until recently, however, that targeting AXL has come under the spotlight because of ever accumulating evidence of its strong correlation with poor prognosis and drug resistance. The entry of the first AXL-branded inhibitor in clinical trials in 2013 marked an important milestone for the clinical validation of AXL as an anticancer target. Nevertheless, to weigh the current contribution and potential future impact of AXL inhibition in the clinic, it is fundamental to recognize that several kinase inhibitors approved or in clinical development have AXL as either a prominent secondary or even the primary target. Through this review, the chemical and biological properties of the main inhibitors targeting AXL (either intentionally or unintentionally) will be discussed, along with the prospects and challenges to translate AXL inhibitors into a bona fide therapeutic option.

Topics: Axl Receptor Tyrosine Kinase; Chemistry, Pharmaceutical; Humans; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases

This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334).. Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (. Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months.. LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Benzimidazoles; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Niacinamide; Prognosis; Ramucirumab

The use of kinase-directed precision medicine has been heavily pursued since the discovery and development of imatinib. Annually, it is estimated that around ∼20 000 new cases of tropomyosin receptor kinase (TRK) cancers are diagnosed, with the majority of cases exhibiting a TRK genomic rearrangement. In this Perspective, we discuss current development and clinical applications for TRK precision medicine by providing the following: (1) the biological background and significance of the TRK kinase family, (2) a compilation of known TRK inhibitors and analysis of their cocrystal structures, (3) an overview of TRK clinical trials, and (4) future perspectives for drug discovery and development of TRK inhibitors.

Topics: Animals; Antineoplastic Agents; Catalytic Domain; Cell Line, Tumor; Drug Discovery; Humans; Mice, Inbred BALB C; Neoplasms; Precision Medicine; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Receptor, trkA; Receptor, trkB; Receptor, trkC