Discovery of novel tetracyclic compounds as anaplastic lymphoma kinase inhibitors

Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review

“…Key changes to boost ALK inhibition were replacement of furan ring with a pyrrole and of C-3 ethoxy group with a nitrile. Optimization of C-8 basic fragment generated lead compound 45 (enzyme ALK IC 50 = 1.5 nM, Karpas 299 growth inhibition IC 50 = 21.4 nM), which also had improved liver microsome stability [81]. Further optimization identified the C-9 ethyl group to be ideal for improving kinase selectivity, while maintaining ALK inhibitory activity (46: enzyme ALK IC 50 = 2.9 nM, Karpas 299 growth inhibition IC 50 = 12.8 nM).…”

Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: Design, synthesis, and structure—activity relationship study

“…Compared to many medicinal chemistry efforts on the 2,4-diaminopyrimidine scaffold (as in 3) [7,9], limited structural optimization on the benzo[b]carbazolone scaffold (as in 5) has been reported, likely due to the difficulty in chemical synthesis. The currently available SAR on this tetracyclic framework was mostly reported by scientists at the Japanese company Chugai (a subsidiary of Roche) [28][29][30]. From the X-ray co-crystal structure (PDB ID: 3AOX) [31] of the catalytic domain of ALK in complex with 5 (Alectinib) (Figure 2), the tetracylic benzo[b]carbazolone core exists as a planar conformation where the carbonyl group interacts with the backbone NH of Met1199 in the kinase hinge region.…”

“…carbazole-3-carbonitrile (30) To a solution of compound 6b (1 g, 2.27 mmol) in EtOH (9 mL) in a sealed tube,…”

“…Therefore, the current strategy to the development of second-generation ALK inhibitors to combat the acquired resistance of Crizotinib is rather dependent on the fine structural tuning on the earlier ALK inhibitors either to elevate the antitumor potency or to identify new structural scaffolds capable of interacting with the secondary mutations, especially the gatekeeper L1196M ( Figure 1). Several structurally distinct small molecules have been developed as the second-generation ALK inhibitors, including PF-06463922 (2) [22][23][24], Ceritinib (3, LDK-378) [25][26][27], Alectinib (5, CH5424802) [10,[28][29][30][31][32], AP26113 [33,34], X-396 [35], TSR-011 [36,37], and so on [7,38]. Among these, Ceritinib and Alectinib have The second-in-class ALK inhibitor 2,4-diaminopyrimidine Ceritinib (3) [25,26] and the third-in-class ALK inhibitor benzo [b]carbazolone Alectinib (5) [28][29][30] represent the two major chemotypes of second-generation ALK inhibitors possessing distinct structural characteristics.…”

Identification of Novel Anaplastic Lymphoma Kinase (ALK) Inhibitors Using a Common Feature Pharmacophore Model Derived from Known Ligands Crystallized with ALK

“…Currently, a number of ALK inhibitors have been reported, and several of them are in clinical trials (12–16). One ALK inhibitor, namely crizotinib (PF‐02341066; Pfizer ® , Pfizer Inc., New York, NY, USA) (17,18), has been approved by US FDA for the treatment for EML4‐ALK‐positive NSCLC.…”