Discovery of new 1H-pyrazolo[3,4-d]pyrimidine derivatives as anticancer agents targeting EGFR^WT and EGFR^T790M

Abstract

New 1 H -pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC 50 values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFR WT ). Compound 12b was the most potent member showing an IC 50 value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFR T790M ) (IC 50 = 0.236 µM). Flow cytometric analyses revealed that compound 12b is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFR WT and EGFR T790M .

Proline‐rich 11 (PRR11) promotes the progression of cutaneous squamous cell carcinoma by activating the EGFR signaling pathway

“…38,39 Mutation, overexpression, and dysregulation of EGFR are highly associated with tumorigenesis and tumor progression of various cancers, including cSCC. 40,41 In combination with our current results, we thought that PRR11 promoted cSCC proliferation, survival, and migration by activating the EGFR signaling pathway. In lung cancer, breast cancer, and esophageal carcinoma, AKT signaling has been identified as a mechanism by which PRR11 promotes tumor progression.…”

“…Eventually, multiple cellular events are changed, such as the cell cycle, apoptosis, cytoskeleton dynamics, cell migration, and cell invasion 38,39 . Mutation, overexpression, and dysregulation of EGFR are highly associated with tumorigenesis and tumor progression of various cancers, including cSCC 40,41 . In combination with our current results, we thought that PRR11 promoted cSCC proliferation, survival, and migration by activating the EGFR signaling pathway.…”

Novel 2-Thiouracil-5-Sulfonamide Derivatives: Design, Synthesis, Molecular Docking, and Biological Evaluation as Antioxidants with 15-LOX Inhibition

“…Numerous pyrimidine medicines have a range of therapeutic properties like anticancer such as 5-fluorouracil (5-FU), antiviral such as Idoxuridine and Trifluridine, anti-HIV such as Zidovudine and Stavudine, antibacterial such as Trimethoprim, Sulphamethiazine, and Sulphadiazine, antihypertensive such as Minoxidil and Prazosin, antithyroid such as Propylthiouracil, and antibiotic such as Bacimethrine [ 20 ]. Pyrimidine is a crucial component of nucleic acids, and it is used in pharmaceutics as a building block for the synthesis of anti-inflammatory, anti-hypertensive, antioxidant, anti-SARS [ 21 , 22 , 23 ], antiviral [ 24 ], anticancer [ 25 ], and antibacterial agents [ 26 ].…”

An Efficient Approach for the Synthesis and Antitumor Evaluation of Novel Azo‐ and Anil‐Linked with 3‐Aminopyrazolo[3,4‐b]pyridine

“…They are used as CDK‐2 [1] and GSK‐3 inhibitors [2] antidepressant, [3] anti‐inflammatory, [4] antihyperglycemic, [5] antitumor, [6] antibacterial, [7] and anxiolytic [8] . They are also utilized to treat Alzheimer's disease, drug addiction, and infertility [9,10] . Additionally, pyrazolopyridine derivatives serve as essential precursors for natural and synthetic bioactive compounds (Figure 1).…”