Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

Abstract

Myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins are promising targets for cancer therapy. Here, we investigated the structure–activity relationships (SARs) and performed molecular docking analysis of renieramycin T (RT) and its analogues and identified the critical functional groups of Mcl-1 targeting. RT have a potent anti-cancer activity against several lung cancer cells and drug-resistant primary cancer cells. RT mediated apoptosis through Mcl-1 suppression and it also reduced the level of Bcl-2 in primary cells. For SAR study, five analogues of RT were synthesized and tested for their anti-cancer and Mcl-1- and Bcl-2-targeting effects. Only two of them (TM-(–)-18 and TM-(–)-4a) exerted anti-cancer activities with the loss of Mcl-1 and partly reduced Bcl-2, while the other analogues had no such effects. Specific cyanide and benzene ring parts of RT’s structure were identified to be critical for its Mcl-1-targeting activity. Computational molecular docking indicated that RT, TM-(–)-18, and TM-(–)-4a bound to Mcl-1 with high affinity, whereas TM-(–)-45, a compound with a benzene ring but no cyanide for comparison, showed the lowest binding affinity. As Mcl-1 helps cancer cells evading apoptosis, these data encourage further development of RT compounds as well as the design of novel drugs for treating Mcl-1-driven cancers.

Novel Synthetic Derivative of Renieramycin T Right-Half Analog Induces Apoptosis and Inhibits Cancer Stem Cells via Targeting the Akt Signal in Lung Cancer Cells

“…In addition, the investigation of the apoptotic-related proteins also revealed that DH_25 diminished the expression of the anti-apoptotic protein Mcl-1 and partly decreased Bcl-2 levels ( Figure 3 C). This finding adds to previous research that both the cyanide and benzene rings of RT analogs are essential for Mcl-1-targeting activity [ 21 ]. This study suggests that even if the benzene ring is modified to thiazole, the Mcl-1-suppression effect is preserved.…”

“…The IC 50 values of DH_16, DH_19, and DH_22 were comparable at 14–20 µM. Moreover, when TM-(–)-4a, the most potent compound in a previous study [ 21 ], was applied for comparison, DH_25 even showed a lower IC 50 than TM-(–)-4a, whose IC 50 in H460 cells was 9.5 ± 2.78 µM ( Figure 1 C).…”

“…Cyanide and a benzene ring of the RT analog are necessary components for the interaction with Mcl-1, as indicated by further studies of SARs [ 21 ]. However, the IC 50 of the Mcl-1-targeted RT right-half analogs was quite high compared with that of the parent compound.…”

“…Consequently, five right-half RT analogs were synthesized to study their structure–activity relationships (SARs) and identify active moieties that are essential for drug action. Results of the study indicated that the cyanide and benzene ring compositions of RT play an important role in targeting Mcl-1 [ 21 ]. Based on these findings, novel synthetic derivatives of RT right-half analogs were developed by modifying the other part of structure, including the ring part, with the remaining cyanide to explore the SARs and improve the anticancer effects.…”

Aspiletrein A Induces Apoptosis Cell Death via Increasing Reactive Oxygen Species Generation and AMPK Activation in Non-Small-Cell Lung Cancer Cells

“…In addition, the apoptosis-inducing effect of AA and its molecular mechanism were confirmed in patient-derived lung cancer cells. The experiment in patient-derived cancer cells is widely accepted as an alternative approach in cancer research that minimizes animal use and provides precise molecular mechanisms mimicking humans and corresponding to the clinical response [ 52 , 53 , 54 , 55 ]. The in vitro 3D-tumorigenesis model provided an adequate cancer microenvironment, in which the cancer spheroid grown on matrix-like substance displays is ultimately functional of the cells and approximately relevant to the cancer microenvironment context [ 56 , 57 , 58 ].…”