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326 results on '"Agrawal, Ashish Kumar"'

21. Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy.

Author

Mitra, Rangan, Kumar, Sandeep, Chaudhuri, Aiswarya, Agrawal, Ashish Kumar, and Ayyannan, Senthil Raja

Subjects
CANCER treatment, CYTOTOXINS, ACETAMIDE, THIADIAZOLES, CELL cycle, OXIDATIVE stress, LIBRARY design & construction
Abstract

Src homology‐2 (SH2) domain‐containing phosphatase‐2 (SHP2), the first protooncogenic phosphatase is a key mediator in the development and progression of various cancers. Several allosteric sites have been identified in SHP2, inhibitors of which are being developed. In the current study, we have designed and synthesized a library of 21 thioacetamide‐tethered thiadiazole‐1,2,4‐triazole hybrids (compounds 16–36) and evaluated their in vitro SHP2 inhibitory potential. Compound 28 (N‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐1,3,4‐thiadiazol‐2‐yl)‐2‐((5‐(4‐methoxyphenyl)‐4H‐1,2,4‐triazol‐3‐yl)thio)acetamide) emerged as the most potent SHP2 inhibitor (IC50=0.318±0.001 μM) inhibiting the enzyme in a mixed to non‐competitive manner. In silico studies revealed that the lead inhibitor strongly binds to the tunnel allosteric site of SHP2. Further, cytotoxicity studies revealed that compound 28 caused death of SHP2‐driven MCF‐7 (GI50=37.02±0.25 μM) and U87MG cells (GI50=68.69±0.21 μM) in a dose‐dependent manner and inhibited MCF‐7 cell colony formation and migration. Flow cytometric analysis showed that it exerted its antiproliferative effect on U87MG cells by inducing early apoptosis (Q2 phase) and inhibiting cell cycle progression at the G1 and S phase. Compound 28 was shown to increase oxidative stress in the U87 cells by promoting ROS generation and loss of mitochondrial integrity. In summary, the present study produced a potent SHP2 inhibitor (compound 28) with a promising in vitro cytotoxicity profile, thus meriting further investigation. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Combinatorial Delivery of Docetaxel- and Erlotinib-Loaded Functionalized Nanostructured Lipid Carriers for the Treatment of Triple-Negative Breast Cancer Using Quality-by-Design Approach.

Author

Chaudhuri, Aiswarya, Kumar, Dulla Naveen, Srivastava, Saurabh Kumar, Kumar, Dinesh, Patil, Umesh Kumar, Parmar, Avanish Singh, Singh, Sanjay, and Agrawal, Ashish Kumar

Subjects
TRIPLE-negative breast cancer, FOLIC acid, ANTINEOPLASTIC agents, ZETA potential, ERLOTINIB, DOCETAXEL
Abstract

This study explored the combined administration of docetaxel (DOC) and erlotinib (ERL) using nanostructured lipid carriers (NLCs), with folic acid (FA) conjugation to enhance their synergistic anticancer efficacy against triple-negative breast cancer. NLCs were developed through hot melt homogenization–ultrasound dispersion, and optimized by a quality-by-design (QbD) approach using Plackett–Burman design and Box–Behnken design. Plots were generated based on maximum desirability. Spherical, nanosized dispersions (<200 nm) with zeta potential ranging from −16.4 to −14.15 mV were observed. These nanoformulations demonstrated ~95% entrapment efficiency with around 5% drug loading. Stability tests revealed that the NLCs remained stable for 6 months under storage conditions at 4 °C. In vitro release studies indicated sustained release over 24 h, following Higuchi and Korsmeyer–Peppas models for NLCs and FA NLCs, respectively. Additionally, an in vitro pH-stat lipolysis model exhibited a nearly fivefold increase in bioaccessibility compared to drug-loaded suspensions. The DOC–ERL-loaded formulations exhibited dose- and time-dependent cytotoxicity, revealing synergism at a 1:3 molar ratio in MDA-MB-231 and 4T1 cells, with combination indices of 0.35 and 0.37, respectively. Co-treatment with DOC–ERL-loaded FA NLCs demonstrated synergistic anticancer effects in various in vitro assays. [ABSTRACT FROM AUTHOR]

Published
2024
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