Similarly compound was prepared from aldehyde
Similarly, Butaprost 13 was prepared from aldehyde 8d by following similar procedures (Scheme 3). Condensation of 13 with 7b or 7e provided the corresponding amides 9j or 9k, which then went through O-debenzylation by BCl3 to deliver the final compounds 10j and 10k in 37% and 32% overall yields, respectively.
Results and disscussion
Conclusion Rather than by focusing on the ever-changing ALK mutants, here we described a new strategy to address the drug resistance of ALK kinase inhibitors by developing ALK/Hsp90 dual targeting inhibitors. Since Hsp90 plays a very important role in maintaining the conformation, stability and function of numerous signaling proteins and its client proteins including many key oncogenic proteins, such as Her2, AKT, and ALK, inhibiting Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. On the basis of our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387, several series of dual inhibitors containing both resorcinol and 2,4-diaminopyrimidine motifs bearing various linkers on different linking sites were developed. Compounds 10h and 10j exhibited high potency against ALK (17.3 vs 9.8 nM) and Hsp90 (100 vs 40 nM). Both compounds showed moderate antiproliferative effects against various cancer cells, but high potency was observed on the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism was confirmed by their down-regulation of the Hsp90 clients ALK and AKT, and up-regulation of the chaperone protein Hsp70 in H3122 cell.
Acknowledgement This work was supported by grants from Chinese NSF (Grants 81430080, 81703327,81773565). Supporting grants from the International Cooperative Program (Grant GJHZ1622) and Key Program of the Frontier Science (Grant 160621) of the Chinese Academy of Sciences, the Shanghai Commission of Science and Technology (Grants 16XD1404600, 14431900400) are also highly appreciated.
Introduction A small group of non–small-cell lung cancer (NSCLC) is characterized by the presence of the anaplastic lymphoma kinase (ALK) fusion oncogene, which defines a distinct clinicopathologic subset of NSCLC. The identification of ALK translocation is crucial because positive tumors are highly sensitive to therapy with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first TKI tested in NSCLC patients with ALK rearrangement and has shown higher efficacy than standard chemotherapy in first- as well as second-line treatment. Nevertheless, after a median of 9 to 10 months, disease progression (PD) inevitably occurs because of acquired resistance. Several distinct mechanisms of resistance have been reported in the literature: appearance of a secondary mutation within the ALK tyrosine kinase domain (ie, p.G1269A, p.I1174N, p.L1196M), amplification of the ALK fusion gene (alone or in combination with a secondary resistance mutation), and activation of alternative signaling pathways. These include abnormalities in the epidermal growth factor receptor (EGFR), tyrosine-protein kinase kit (KIT), and insulin-like growth factor-1 receptor pathways and suggest the potential need for combination therapies to overcome resistance. Moreover, also pharmacokinetic mechanisms (ie, brain penetration) could be responsible for PD. Notably, patients resistant to crizotinib can be sensitive to other TKIs of recent development such as ceritinib, alectinib, and brigatinib. Also these new generation ALK TKIs realize a selective pressure on neoplastic clones that can induce acquired resistance. The spectrum of ALK mutations responsible for acquired resistance in ALK-rearranged NSCLC is heterogeneous and none of the ALK TKIs under investigation present the formal indication for a specific resistance mutation. Interestingly, each ALK TKI shows different potency with respect to the point mutation, suggesting a possible clinical algorithm in the future. Recently, Shaw et al reported the case of a patient with ALK-rearranged NSCLC who developed liver metastasis during crizotinib treatment and presented the p.C1156Y ALK mutation, conferring sensitivity to lorlatinib. The treatment with lorlatinib determined the selection of a double mutant clone (p.C1156Y/p.L1198F) that conferred resistance to this drug, but was able to revert sensitivity to crizotinib.