Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Alectinib is a second generation ALK

    2022-10-27

    Alectinib is a second generation ALK antagonist that is built upon a 9-ethyl-6, 6-dimethyl-11-oxo benzo[b]carbazole scaffold (Fig. 5C) [58]. This drug is effective against the ALK L1196M gatekeeper mutation along with C1156Y and F1174L mutations [7]. The 11-oxo group of the drug forms a LJI308 with the NH group of ALK M1199 of the hinge (Fig. 6C). Alectinib makes hydrophobic contacts with L1122 at the end of the β1-strand, A1148 (CS8), V1180 (Sh1), the gatekeeper L1196 (Sh2), L1182 within the hinge, and L1256 (CS6). L1122 and A1148 occur above the plane of the scaffold while L1256 occurs below the plane. These residues are found within the front pocket and BP-I-B in the gate area [48]. The 4-morpholin-4-piperidine group extends from the enzyme into the solvent. The αC-E1167 forms a hydrogen bond with the β3-K1150, the R-spine is linear, and DFG-D1270 is pointed toward the active site, properties associated with an active enzyme form. However, the activation segment has an αAL helix indicating that the segment is in the compact conformation of a dormant enzyme. Binding to the front pocket of an inactive enzyme with the DFG-D in conformation indicates that alectinib is a type I½ B inhibitor. Alectinib is a second-line treatment that is FDA-approved for the treatment of crizotinib-resistant ALK+-NSCLC (www.brimr.org/PKI/PKIs.htm). Brigatinib is an ALK antagonist with a bisanilinopyrimidine scaffold and piperazine and piperidine extensions (Fig. 5D). This drug is effective against most crizotinib-resistant mutants including C1156Y, F1174L, L1196M (the gatekeeper), G1202R, and R1275Q [59]. The N3 of the pyrimidine forms a hydrogen bond with the NH group of M1199 of the hinge while the phenylamino group forms a hydrogen bond with the M1199 carbonyl group (Fig. 6D). The drug makes hydrophobic contacts with L1122 before the glycine-rich loop, V1130 (CS7) after the loop, A1148 (CS8), L1196/1198 of the hinge, L1256/1257 (CS6/5), and V1265 before the activation segment. The 5-chloropyridine component of brigatinib makes hydrophobic contacts with A1148 in the ceiling of the cleft and with L1256 in the floor. The methoxy group binds under hinge residue L1198 and the piperazine-piperidine solubilization moieties extend from the enzyme into the solvent. Owing to an intramolecular hydrogen bond between the scaffold and the C4 aniline NH group, brigatinib pays a reduced entropic penalty during the formation of the drug-enzyme complex. The drug is found in the adenine pocket and the adjacent FP-I region of the front cleft [48]. The binding pattern of brigatinib with ALK classifies it as a type I½ B antagonist. This medicinal is in four clinical trials for the treatment of ALK+-NSCLC, but it has not been FDA-approved. Entrectinib, which is a brain penetrant type I½ B ALK inhibitor, contains an indazole scaffold (Fig. 5E) [60]. The drug is effective against the ALK crizotinib-resistant L1196M gatekeeper mutation, but not against the G1202R mutant. The NH group of the indazole forms a hydrogen bond with the carbonyl group of E1197 while its N1 forms a hydrogen bond with M1199, both residues of which occur within the hinge. The amino group attached to the 3-position of indazole forms a hydrogen bond with the carbonyl group of M1199. The antagonist makes numerous hydrophobic contacts with ALK including L1122 before the glycine-rich loop, F1127 within the G-rich loop, V1130 (CS7) in the β1-strand following the G-rich loop, A1148 (CS8), V1180 (Sh1), I1183 in the αC-β4 loop, the gatekeeper L1196 (Sh2), L1198 within the hinge, the catalytic loop N1254, and the 1255CLL1257 triad (CS4/6/5) after the catalytic loop. The indazole group makes hydrophobic contact with V1130 and A1148 in the ceiling of the cleft and with L1256 in the floor. The 3,5-difluorophenyl group of the medicinal makes hydrophobic contact with F1127 in front of the aromatic group, with D1203 at its bottom, and C1255 and L1256 at its rear (as protein kinases are classically viewed). The drug also makes van der Waals contact with DFG-D1270. The tetrahydropyran and the N-methylpiperazinyl solubilizing group extend from the protein into the solvent. The drug occupies the adenine pocket and the adjacent FP-I region of the front cleft [48] and is classified as a type I½ B antagonist. Entrectinib is in four clinical trials against malignancies driven by its target kinases including Trk1/2/3, ROS1, and ALK [7].