Department Of Pharmaceutical Sciences and Natural Products
Permanent URI for this communityhttps://kr.cup.edu.in/handle/32116/52
Browse
5 results
Search Results
Item Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities(American Chemical Society, 2023-02-22T00:00:00) Maity, Pritam; Chatterjee, Joydeep; Patil, Kiran T.; Arora, Sahil; Katiyar, Madhurendra K.; Kumar, Manvendra; Samarbakhsh, Amirreza; Joshi, Gaurav; Bhutani, Priyadeep; Chugh, Manoj; Gavande, Navnath S.; Kumar, RajEpidermal growth factor receptor (EGFR) is an oncogenic drug target and plays a critical role in several cellular functions including cancer cell growth, survival, proliferation, differentiation, and motility. Several small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) have been approved for targeting intracellular and extracellular domains of EGFR, respectively. However, cancer heterogeneity, mutations in the catalytic domain of EGFR, and persistent drug resistance limited their use. Different novel modalities are gaining a position in the limelight of anti-EGFR therapeutics to overcome such limitations. The current perspective reflects upon newer modalities, importantly the molecular degraders such as PROTACs, LYTACs, AUTECs, and ATTECs, etc., beginning with a snapshot of traditional and existing anti-EGFR therapies including small molecule inhibitors, mAbs, and antibody drug conjugates (ADCs). Further, a special emphasis has been made on the design, synthesis, successful applications, state-of-the-art, and emerging future opportunities of each discussed modality. � 2023 American Chemical Society.Item FDA approved five-membered ring fused pyrimidine-based derivatives and their biological properties(Elsevier, 2022-10-14T00:00:00) Kumar, Manvendra; Chatterjee, Joydeep; Rani, Dimpy; Kumar, RajPyrimidines-based drugs are one of the most important drugs for novel and recurring viruses, including the coronavirus. This chapter deals with 41 FDA-approved five-membered ring fused pyrimidine-based drugs, their synthetic strategies, and pharmacological activities. � 2023 Elsevier Ltd. All rights reserved.Item In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-a]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice(MDPI, 2022-08-30T00:00:00) Bhat, Zahid Rafiq; Kumar, Manvendra; Sharma, Nisha; Yadav, Umesh Prasad; Singh, Tashvinder; Joshi, Gaurav; Pujala, Brahmam; Raja, Mohd; Chatterjee, Joydeep; Tikoo, Kulbhushan; Singh, Sandeep; Kumar, RajTyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes. � 2022 by the authors.Item Design and synthesis of non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of EGFR and their anti-cancer assessment(MDPI AG, 2021-03-09T00:00:00) Kumar, Manvendra; Joshi, Gaurav; Arora, Sahil; Singh, Tashvinder; Biswas, Sajal; Sharma, Nisha; Bhat, Zahid Rafiq; Tikoo, Kulbhushan; Singh, Sandeep; Kumar, RajA series of 30 non-covalent imidazo[1,2-a]quinoxaline-based inhibitors of epidermal growth factor receptor (EGFR) were designed and synthesized. EGFR inhibitory assessment (against wild type) data of compounds revealed 6b, 7h, 7j, 9a and 9c as potent EGFRWT inhibitors with IC50 values of 211.22, 222.21, 193.18, 223.32 and 221.53 nM, respectively, which were comparable to erlotinib (221.03 nM), a positive control. Furthermore, compounds exhibited excellent antiproliferative activity when tested against cancer cell lines harboring EGFRWT; A549, a non-small cell lung cancer (NSCLC), HCT-116 (colon), MDA-MB-231 (breast) and gefitinib-resistant NSCLC cell line H1975 harboring EGFRL858R/T790M. In particular, compound 6b demonstrated significant inhibitory potential against gefitinib-resistant H1975 cells (IC50 = 3.65 �M) as compared to gefitinib (IC50 > 20 �M). Moreover, molecular docking disclosed the binding mode of the 6b to the domain of EGFR (wild type and mutant type), indicating the basis of inhibition. Furthermore, its effects on redox modulation, mitochondrial membrane potential, cell cycle analysis and cell death mode in A549 lung cancer cells were also reported. Copyright: � 2021 by the authors. Licensee MDPI, Basel, Switzerland.Item Coumarin Derivatives as Anticancer Agents for Lung Cancer Therapy: A Review.(Bentham Science, 2018) Kumar, Manvendra; Singla, Ramit; Jandriyal, Jyoti; Jaitak, VikasBackground: The prevalence of lung cancer is 14% among the newly diagnosed cancer cases worldwide. Currently, the number of drugs that are in clinical practice is having a high prevalence of side effect and multidrug resistance. Researchers have made an attempt to expand a suitable anticancer drug that has no MDR and side effect. Objective: Extensive exploration of Coumarin derivatives as a potent inhibitor of variety of proteins including EGFR, tyrosine kinase, ERK1/2, PI3K, HSP 90, Bax, STAT proteins, NF-κB and telomerase which have been associated with lung cancer. Method: The recent literature was surveyed utilizing the online resources and databases including scifinder, pubchem, EMBL, scopus and google scholar. Results: Upon analyzing the structure-activity relationship, it was found that N-aryl carboxamide, phenyl substitution at the C-3 position and 1,2,3- triazolyl, trihydroxystilbene, amino substitution at the C-4 position of the coumarin nucleus were the most effective in targeting lung cancer. Conclusion: This review is a collaborative and extensive compilation of synthetic strategies, mechanism of action, and the structure-activity relationship thereof for the management of lung carcinoma.