New Genetic Bomb Trigger: Design, Synthesis, Molecular Dynamics Simulation, and Biological Evaluation of Novel BIBR1532-Related Analogs Targeting Telomerase against Non-Small Cell Lung Cancer

Abstract

Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, telomere restoration occurs in cancer cells because of telomerase activation or alternative telomere lengthening. The telomerase enzyme is a universal anticancer target that is expressed in 85–95% of cancers. BIBR1532 is a selective non-nucleoside potent telomerase inhibitor that acts by direct noncompetitive inhibition. Relying on its structural features, three different series were designed, and 30 novel compounds were synthesized and biologically evaluated as telomerase inhibitors using a telomeric repeat amplification protocol (TRAP) assay. Target compounds 29a, 36b, and 39b reported the greatest inhibitory effect on telomerase enzyme with IC50 values of 1.7, 0.3, and 2.0 μM, respectively, while BIBR1532 displayed IC50 = 0.2 μM. Compounds 29a, 36b, and 39b were subsequently tested using a living-cell TRAP assay and were able to penetrate the cell membrane and inhibit telomerase inside living cancer cells. Compound 36b was tested for cytotoxicity against 60 cancer cell lines using the NCI (USA) procedure, and the % growth was minimally impacted, indicating telomerase enzyme selectivity. To investigate the interaction of compound 36b with the telomerase allosteric binding site, molecular docking and molecular dynamics simulations were used.

Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin’s Lymphoma Cell Death

“…Exposure of HDLM-2, L-428 and L-1236 HL cell lines to 4 nM of trabectedin [ 27 ] (ALT pathway inhibitor) or 200 µM of BIBR1532 (telomerase inhibitor) [ 48 ] for 144 h led to a time-dependent decrease in cell viability. As shown in Figure 3 , all three cell lines exhibited a reduction in cell viability.…”

“…BIBR1532 has been used in several studies as a specific and powerful telomerase inhibitor [ 48 , 73 , 74 , 75 ]. It demonstrates anti-migration and anti-proliferation properties in addition to its cytotoxic effect on cancer cells [ 76 , 77 ].…”

Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

“…Obviously, 85–90% of human cancers are associated with telomerase enzyme reactivation to preserve the chromosomal ends, leading to unlimited tumor cell proliferation. Numerous types of human malignancies, such as the colon, breast, cervix, liver, kidney, lung, pancreas, prostate, thyroid, and urinary bladder cancers, have been associated with telomerase activity …”

“…Direct telomerase inhibitors may either be small molecule inhibitors (e.g., BIBR1532) and act on hTERT or oligonucleotide inhibitors (e.g., Imetelstat) that act on hTERC . However, indirect telomerase inhibitors (e.g., Thio-dG (6-thio-20-deoxyguanosine)) and G-quadruplex stabilizers (e.g., BRACO-19 and Telomestatin) can be regarded as telomere-disrupting nucleoside analogues, as depicted in Figure . ,, …”

“…Hence, telomerase is one of the outstanding biological targets for cancer treatment . Being a ribonucleoprotein enzyme with reverse transcriptase activity, telomerase can synthesize telomere DNA sequences using its RNA as a template .…”