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    • Lorlatinib is an orally active brain penetrant cyclic

    2022-12-02

    Lorlatinib is an orally active brain penetrant cyclic 2-aminopyridine derivative that is a type I½ B ALK inhibitor (Fig. 5F) [61]. This medicinal is an effective antagonist against the more common L1196M and G1269A crizotinib-resistant mutations as well as the less common T1151Ins, L1152R, C1156Y, F1174L, and S1206Y mutants [62]. The X-ray structure shows that the 2-amino group forms a hydrogen bond with Ell97 of the hinge and the N1 of the pyridine ring forms a hydrogen bond with the NH group of M1199. Note that these interactions with the first and third hinge residues correspond to the mode of interaction of the DL-AP5 synthesis group of ADP with ALK (Fig. 2A). The drug makes hydrophobic contact with L1122 immediately before the glycine-rich loop, V1130 (CS7) near the beginning of the β2-strand, A1148 (CS8), V1180 (Sh1), L1196/1198 within the hinge, N1254 at the end of the catalytic loop, and L1256 (CS6). The pyridine group makes hydrophobic contact with A1148 in the ceiling and L1256 of the floor of the cleft while the pyrazole group makes hydrophobic contact with L1122 in the ceiling. The fluorobenzene component of the drug makes van der Waals contact with R1253 and N1254 and hydrophobic contact with L1256, all in the floor of the cleft. Lorlatinib also makes van der Waals contact with DFG-D1270. The drug occupies the adenine pocket and the adjacent FP-I region of the front cleft [48]. The pyrazole with its methyl and cyano attachments extend from the enzyme into the solvent. Lorlatinib is in three clinical trials in patients with ALK+ or ROS1+ lung cancer including treatment of related brain metastases. Lung cancer accounts for nearly one-half of all cancer metastases to the brain and lorlatinib was fabricated to traverse the blood brain barrier [61].
    Mechanisms of ALK-based drug resistance The replacement of the ALK methionine gatekeeper with leucine does not confer crizotinib resistance by blocking access to the back pocket as seen in the X-ray structure of the drug bound to the L1196M G1269A double mutant (PDB ID: 4ANS). Lovly et al. observed that the EML4-ALK 1196M fusion protein exhibits greater cellular baseline levels of phosphorylation than the wild type protein indicating that this gatekeeper mutation leads to increased protein kinase activity [63]. This observation suggests that the replacement of leucine with methionine stabilizes the ALK active conformation and leads to drug resistance. Recall that the gatekeeper (Sh2) occurs near the top of the regulatory spine, and it is likely that the replacement of leucine with methionine strengthens the R-spine and tips the equilibrium in favor of active ALK. Accordingly, crizotinib resistance results from enzyme activation and not from steric hindrance or to the blockade of the back pocket by the gatekeeper. Several other ALK crizotinib-resistant mutations have been identified in tumor samples from patients with NSCLC [64]. Val1180 is the Sh1 residue that occurs in the αC-β4 loop (Fig. 7). Its mutation to the larger leucine (V1180L) may hinder drug binding. Asp1203, which is in direct contact with crizotinib, is on the floor of the drug binding site. Although the size difference between aspartate and the mutant asparagine (D1203N) is marginal, models indicate that the asparagine obstructs crizotinib binding. The S1206Y mutation is located on the floor of the crizotinib binding site and the conversion of the small serine to the larger tyrosine may block its binding. Similarly, the G1269A mutation occurs on the floor of the drug binding site immediately before 1270DFG1272 and the larger alanine may prevent enzyme-drug complex formation. The I1171T is the RS3 residue that occurs within the αC-helix; perhaps this mutation produces a structural change that strengthens the R-spine leading to a more active enzyme. However, this suggestion is counter intuitive because threonine is less hydrophobic than isoleucine. The L1152R mutation occurs in the β3-strand, the C1156Y mutation occurs within the β3–αC loop just before the αC-helix, the F1174L mutation occurs within the αC-helix, and the S1206Y and E1210K mutations occur within the αD-helix; in each of these cases the residues are too far to directly block crizotinib binding. The mechanism for conferring resistance to crizotinib is unclear in these situations, but it may result from the destabilization of the inactive enzyme conformation that readily forms a complex with the drug.