Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry 2024-12, Vol.39 (1), p.2388209
• Main Authors: Gamal, Hassan, Ismail, Khadiga A, Omar, A-Mohsen M E, Teleb, Mohamed, Abu-Serie, Marwa M, Huang, Sun, Abdelsattar, Abdalla S, Zamponi, Gerald W, Fahmy, Hesham
• Format: Article
• Language: English
• Subjects: adjuvant therapy; Adjuvants; Antifungal agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antioxidants; Calcium channels (T-type); Calcium Channels, T-Type - metabolism; Calcium signalling; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Proliferation - drug effects; Chemistry; Chemotherapy; Cisplatin; Cisplatin - chemistry; Cisplatin - pharmacology; Cytotoxicity; Dose-Response Relationship, Drug; Drug resistance; Drug Screening Assays, Antitumor; Enzymes; Extracellular matrix; Gelatinase B; Humans; Hybrids; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - chemical synthesis; Matrix Metalloproteinase Inhibitors - chemistry; Matrix Metalloproteinase Inhibitors - pharmacology; MMP-9; Molecular Structure; Non-small cell lung carcinoma; Oxidative stress; Pharmaceutical sciences; Pharmacy; Platinum; Small cell lung carcinoma; Stem cells; Stromelysin 2; Structure-Activity Relationship; T-type calcium channel; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Toxicity; Triazoles; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology
• ISSN: 1475-6366; 1475-6374; 1475-6374
• DOI: 10.1080/14756366.2024.2388209

Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that has a balanced profile of cytotoxicity (IC  = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 μM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC  = 90 ± 7 nM) surpassing NNGH with MMP-9 over -2 and MMP-10 over -13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.