9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors

Abstract

9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.

Discovery of 2-arylamino-4-(1-methyl-3-isopropylsulfonyl-4-pyrazol-amino)pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors

“…In addition, the targets 29f and 29g with carbon attached to the phenyl ring directly were 3 to 5 folds less potent, demonstrating the importance of oxygen linkage. Based on the structure of ALK and known literatures, 10,18 we believe that the relatively bulky R 1 substitutions in Table 1 should provide good ALK selectivities and these will be studied in the future.…”

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

“…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.…”

“…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.…”

“…In view of the structural novelty of 5, we decided to conduct an additional medicinal chemistry campaign by either inserting a linker within the side chain (series I, II and IV) or by opening the middle ketone ring (series III), thus leading to four series of new compounds with relatively more rotatable bonds and higher molecular flexibility. precursor 7a in additional five steps by following literature procedures [28,29].…”

“…Alkylation of 7c with 4-(bromomethyl)tetrahydro-2H-pyran under the similar reaction condition as that for preparation of 12 and 13 provided compound 11 in 54% yield. Meanwhile, compound 15f was prepared by reductive amination of 7d with oxetan-3-one in 46% overall yield [28,29].…”