Modulation of DNA damage response by targeting ATM kinase using newly synthesized di-phenoxy acetamide (DPA) analogs to induce anti-neoplasia

• Published in: Pharmacological reports Vol. 73; no. 5; p. 1344
• Main Authors: Al-Ostoot, Fares Hezam, Sherapura, Ankith, Malojirao, Vikas H, Thirusangu, Prabhu, Al-Muhimeed, Tahani I, Khanum, Shaukath Ara, Prabhakar, B T
• Format: Journal Article
• Language: English
• Published: Switzerland 01-10-2021
• Subjects: Acetamides - chemical synthesis; Acetamides - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis; Cell Line, Tumor; DNA Damage; DNA Repair; Drug Delivery Systems; Humans; Mice; Mice, Inbred BALB C; Molecular Structure; Neoplasms, Experimental - drug therapy; Xenograft Model Antitumor Assays; Anti-neoplasia; Di-phenoxy acetamide analogs; DDR; ATM kinase; Apoptosis
• ISSN: 1734-1140
• DOI: 10.1007/s43440-021-00292-6

Imbalance and instability in the structure of the DNA have become major characteristics of cancer. In response to DNA damage, DNA damage response (DDR) protein, ataxia telangiectasia mutated (ATM), plays a pivotal role in the modulation of regulatory regions responsible for inhibition of apoptosis, thereby neoplastic progression.
A new series of DPA (7a-t) were synthesized, characterized. Anti-proliferative studies to identify the lead compound were carried out by LDH and MTT assay. Apoptosis/DNA damage was measured through FACS, Annexin-v staining, TUNEL and Comet assay. Elucidation of molecular mechanism through immunoblot and further validation of the drug effect through in vivo approaches.
Initial in vitro anti-proliferative screening of Compounds DPA (7a-t) against multiple cancer cell lines identified Compound DPA (7n) as a potent cytotoxic molecule with IC
value of 4.3 μM. Down the line, in vitro and in vivo evaluation of Compound DPA (7n) inferred that it has apoptotic inducing potentiality. Further, evaluation of molecular mechanism inferred that Compound DPA (7n) effectively modulates ATM phosphorylation only, eventually altering downstream signalling pathways.
Compound DPA (7n) emerged as a potent proapoptotic and anti-neoplastic agent by inhibiting ATM kinase activity both in vitro and in vivo. The conferring results ascertain that the drug could be developed as a new ATM kinase inhibitor with anti-cancer capacity.