Vinblastine and its derivatives used in clinics as antitumor drugs often cause drug resistance and some serious side effects; thus, it is necessary to study new vinblastine analogues with strong anticancer cytotoxicity and low toxicity. We designed a dimer molecule using two vindoline-bonded dimer vindoline (DVB) and studied its interaction with α,β-tubulin through the double-sided adhesive mechanism to explore its anticancer cytotoxicity. In our work, DVB was docked into the interface between α-tubulin and β-tubulin to construct a complex protein structure, and then it was simulated for 100 ns using the molecular dynamics technology to become a stable and refined complex protein structure. Based on such a refined structure, the quantum chemistry at the level of the MP2/6-31G(d,p) method was used to calculate the binding energies for DVB interacting with respective residues. By the obtained binding energies, the active site residues for interaction with DVB were found. Up to 20 active sites of residues within α,β-tubulin interacting with DVB are labeled in β-Asp179, β-Glu207, β-Tyr210, β-Asp211, β-Phe214, β-Pro222, β-Tyr224, and β-Leu227 and α-Asn249, α-Arg308, α-Lys326, α-Asn329, α-Ala333, α-Thr334, α-Lys336, α-Lys338, α-Arg339, α-Ser340, α-Thr349, and α-Phe351. The total binding energy between DVB and α,β-tubulin is about −251.0 kJ·mol –1 . The sampling average force potential (PMF) method was further used to study the dissociation free energy (Δ G ) along the separation trajectory of α,β-tubulin under the presence of DVB based on the refined structure of DVB with α,β-tubulin. Because of the presence of DVB within the interface between α- and β-tubulin, Δ G is 252.3 kJ·mol –1 . In contrast to the absence of DVB, the separation of pure β-tubulin needs a free energy of 196.9 kJ·mol –1 . The data show that the presence of DVB adds more 55.4 kJ·mol –1 of Δ G to hinder the normal separation of α,β-tubulin. Compared to vinblastine existing, the free energy required for the separation of α,β-tubulin is 220.5 kJ·mol –1 . Vinblastine and DVB can both be considered through the same double-sided adhesive mechanism to give anticancer cytotoxicity. Because of the presence of DVB, a larger free energy is needed for the separation of α,β-tubulin, which suggests that DVB should have stronger anticancer cytotoxicity than vinblastine and shows that DVB has a broad application prospect.
e15147 Background: The Ataxia-telangiectasia mutated (ATM) gene is an oncosuppressor, which plays an important role in the repair of DNA double-strand breaks (DSBs). The mutation profiles of ATM gene in Chinese solid tumor patients can help understand pathogenesis, prognosis, and identify targets for therapy. Methods: Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in normal-paired samples from 1351 patients with malignancies from January 2021 to October 2022, and alterations including single base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements. Results: ATM gene was altered in 6.8% (92 of 1351) of all solid tumors. The frequency of ATM variations was assessed in multiple cancer types, including non-small cell lung cancer 22% (35/159), endometrial carcinoma 15% (2/13), biliary tract tumor 12.1% (7/58), gastric cancer 10.7% (3/28), prostatic cancer 8.3% (1/12), breast cancer 6.7% (2/30), colorectal cancer 6.5% (11/168), thyroid cancer 6.2% (5/80), cervical carcinoma 5.7% (2/35), prostatic cancer 3.9% (2/51), liver cancer 3% (2/66). A total 102 genetic alterations were identified in 92 patients, including 70 missense mutations (69%), 14 nonsense (14%), 9 splicing (9%), 3 frameshift (3%), 2 deletion (2%), 2 copy number variation (2%). Among these patients, 2 had pathogenic germline ATM heterozygous mutations, including one lung adenocarcinoma and one pancreatic cancer. Furthermore, in our cohort, ATM mutation carriers also owned other actionable mutation, the most frequent one was TP53 (41%), followed by APC (29%), KRAS (23%), MLL3 (22%) and BRCA2 (20%). Conclusions: Our findings indicate that ATM alterations are widely mutated in Chinese multiple cancer types, with specific mutations differing largely among different tumor types. ATM alterations warrant further investigation as predictive biomarkers of response to PARP inhibitors or platinum-based therapy.
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