The protein kinases regulate cellular functions such as transcription, translation, proliferation, growth and survival by the process of phosphorylation. Over activation of signaling pathways play a ...major role in oncogenesis. The PI3K signaling pathway is dysregulated almost in all cancers due to the amplification, genetic mutation of PI3K gene and the components of the PI3K pathway themselves. Stimulation of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK pathways enhances growth, survival, and metabolism of cancer cells. Recently, the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways have been identified as promising therapeutic targets for cancer therapy. The kinase inhibitors with enhanced specificity and improved pharmacokinetics have been considered for design and development of anticancer agents. This review focuses primarily on the Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways as therapeutic targets of anticancer drugs, their specific and dual inhibitors, structure activity relationships (SARs) and inhibitors under clinical trials.
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•PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways have been described.•The pathways inhibitors and their SARs have been described.•The pathways inhibitors under clinical trial have also been described.
The PIM kinase, also known as serine/threonine kinase plays an important role in cancer biology and is found in three different isoforms namely PIM-1, PIM-2, and PIM-3. They are extensively ...distributed and are implicated in a variety of biological processes, including cell proliferation, cell differentiation, and apoptosis. They act as weak oncogene and whenever expressed in exacerbating forms are responsible for different types of human cancer. Recently, different isoforms of PIM kinase have been identified as a clinical biomarker and potential therapeutic target for personalized treatment of advanced cancer. The inhibition of PIM kinase has become a scientific interest and some inhibitors have been developed and/or are under different phases of clinical trials. Several medicinally privileged heterocyclic ring scaffolds such as pyrrole, pyrimidine, thiazolidine, benzofuran, indole, triazole, oxadiazole, and quinoline derivatives have been synthesized and evaluated for their PIM inhibitory activity. This review comprehensively focuses on pharmacological implications of PIM kinases in oncogenesis, structural insights of PIM inhibitors and their structure-activity relationships (SARs).
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1.Implications of PIM in oncogenesis.2.Structural insights of PIM inhibitors.3.Deep insight into structure-activity relationships (SARs).
Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold has gained considerable scientific interest in medicinal chemistry owing to its simple chemistry, ease in synthesizing a variety of derivatives ...and exhibiting a broad range of promising pharmacological activities by modulating several molecular targets. A number of natural and (semi-) synthetic chalcone derivatives have demonstrated admirable anti-inflammatory activity due to their inhibitory potential against various therapeutic targets like Cyclooxygenase (COX), Lipooxygenase (LOX), Interleukins (IL), Prostaglandins (PGs), Nitric Oxide Synthase (NOS), Leukotriene D4 (LTD4), Nuclear Factor-κB (NF- κB), Intracellular Cell Adhesion Molecule-1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), Monocyte Chemoattractant Protein-1 (MCP-1) and TLR4/MD-2, etc. The chalcone scaffold with hydroxyl, methoxyl, carboxyl, prenyl group and/or heterocyclic ring substitution like thiophene/furan/indole showed promising anti-inflammatory activity. In this review, a comprehensive study (from the year 1991 to 2016) on multi-targets of inflammatory interest, related inflammation reactions and their treatment by chalcone-based inhibitors acting on various molecular targets entailed in inflammation, Structure-Activity Relationships (SARs), Mechanism of Actions (MOAs), and patents are highlighted.
Five member heterocyclic 1,3,4-oxadiazole nucleus find unique place in medicinal chemistry and plays significant role in producing anticancer activity. The small and simple 1,3,4-oxadiazole nucleus ...is present in various compounds involved in research aimed at evaluating new products that posses interesting pharmacological properties such as antitumour activity. Mono and 2,5-di-substituted-1,3,4-oxadiazole derivatives have attracted considerable attention owing to their effective biological activity and extensive use. The important mechanism involved during its tumour suppression is related with the inhibition of different growth factors, enzymes and kinases including telomerase enzyme, histone deacetylase (HDAC), methionine aminopeptidase (MetAP), thymidylate synthase (TS), glycogen synthase kinase-3 (GSK), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and focal adhesion kinase (FAK). The focused criteria of this review is to highlights the targeted inhibitory activity of 1,3,4-oxadiazole derivatives and their structure activity relationship to generate potential anticancer agents.
1,3,4-oxadizole derivatives targated on growth factors, enzymes and kinases has been described to improve anticancer properties. Display omitted
•Anti-cancer activity of 1,3,4-oxadizole derivatives.•Telomerase enzyme inhibitors and their SARs.•VEGF inhibitors and their SARs.•EGF inhibitors and their SARs.•Glycogen synthase kinase-3b inhibitors and their SARs.
The discovery of genetic, genomic and clinical biomarkers have revolutionized the treatment option in the form of personalized medicine which allows to accurately predict a person's ...susceptibility/progression of disease, the patient's response to therapy, and maximize the therapeutic outcome in terms of low/no toxicity for a particular patient. Recently, the U.S. Food and Drug Administration has realized the contribution of pharmacogenomics in better healthcare and advocated the consideration of pharmacogenomic principles in making safer and more effective drug. Many anticancer drugs show reduced or no response in cancer patients with tumor specific gene mutations such as B-Raf and K-Ras. The high incidence of K-Ras mutation has been reported in pancreatic, colon, and lung carcinomas. The identification of K-Ras as a clinical biomarker and potential therapeutic target has attracted the scientific community to develop effective and precise anticancer drug. Inhibitors which block farnesylation of Ras have been developed or under clinical trial studies. Tipifarnib, approved by USFDA for the treatment of elderly acute leukemia is a Ras pathway inhibitor. Some peptidomimetics and bi-substrate inhibitors like FTI 276, FTI 277, B956, B1086, L731, L735, L739, L750, BMS-214662, L778123, and L778123 are under clinical trials. Recently mutant K-Ras has been considered as potential biomarker and target for precise cancer therapy. This review focuses primarily on the Ras/Raf/MEK/ERK signaling pathway including K-Ras mutation as therapeutic target, inhibitors and their structure activity relationships (SARs) for the design and development of anticancer agents.
Oncogenic K-Ras as a potential therapeutic target and its inhibitors for personalized cancer treatment have been described. Display omitted
•Many anticancer drugs show reduced response in patients due to genetic mutations.•Oncogenic K-Ras mutation is predominant in pancreatic, colon, and lung carcinomas.•K-Ras is a biomarker and molecular target for personalized cancer treatment.•Various peptidomimetics and bi-substrate inhibitors are under clinical trial(s).
mTOR (mammalian target of rapamycin) is a catalytic subunit composed of two multi-protein complexes that indicate mTORC1 and mTORC2. It plays a crucial role in various fundamental cell processes like ...cell proliferation, metabolism, survival, cell growth, etc. Various first line mTOR inhibitors such as Rapamycin, Temsirolimus, Everolimus, Ridaforolimus, Umirolimus, and Zotarolimus have been used popularly. In contrast, several mTOR inhibitors such as Gedatolisib (PF-05212384) are under phase 2 clinical trials studies for the treatment of triple-negative breast cancer. The mTOR inhibitors bearing heterocyclic moieties such as quinazoline, thiophene, morpholine, imidazole, pyrazine, furan, quinoline are under investigation against various cancer cell lines (U87MG, PC-3, MCF-7, A549, MDA-231). In this review, we summarized updated research related to mTOR inhibitors and their structure-activity relationship, which may help scientists develop potent inhibitors against cancer.
Diabetes mellitus is the global health issue and become an alarming threat in the modern era where human lifestyle gets compromised with modernization. According to the latest statistical report ...2020, USA has 9.47% (31 million among 32.72 cr), China has 8.3% (116.4 million among 139.27 cr) and India has 5.6% (77 million among 135.26 cr) of the diabetic people, indicating that diabetes is more prevailing in developed countries as compared to the developing countries. The number of diabetic patients is rising day by day at a tremendous rate and soon it may affect each and every person in a family. So, there is an urgent need to develop novel entities that can meet the scarcity of present antidiabetic agents. In the last few decades, the sodium-glucose co-transporter 2 (SGLT2) has emerged as a prominent target for the treatment of Type 2 diabetes mellitus due to its novel mechanism of action & no involvement in insulin signaling pathway. Most of the inhibitors that target SGLT2 contain three basic moieties: glucose, two benzene rings (one is connected with glucose and the other with methylene), and the methylene bridge which are similar to dapagliflozin. Several SGLT2 inhibitors and their derivatives such as remogliflozin etabonate (phase-II), sotagliflozin (phase-III) and bexagliflozin (phase-III) are under different phases of clinical trial studies and some have been patented. The present review is focused on SGLT2 inhibitors, structure activity relationships (SARs) of dapagliflozin and its several analogues for their binding affinity with SGLT2. We have also presented and summarized the efforts made by various researchers in terms of the synthesis of various dapagliflozin derivatives till date.
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•Global impact in terms of statistical overview regarding type2 diabetes mellitus.•hSGLT2 as potential target for development of novel anti-diabetic agents.•Structural insights of hSGLT2and its inhibitors.•SAR studies to know the effect of different substituents of SGLT2 inhibitors.
Presently, several protein kinases have been discovered with the aim to treat various cancers. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that plays a role in the pathogenesis of ...a wide variety of human cancers known as ALCLs, NSCLC, ovarian cancer, breast cancer, colorectal cancer, neuroblastoma, etc. The fulllength ALK receptor is a classical receptor tyrosine kinase composed of an amino-terminal extracellular domain and an intracellular tyrosine kinase domain. Crizotinib is a strong oral small-molecule first tyrosine kinase inhibitor of ALK to be used in the treatment of ALK-dependent NSCLC. Due to the drug resistance of first generation ALK inhibitors, researchers are trying to design and synthesize novel ALK inhibitors with various heterocyclic rings in which 2,4- diarylaminopyrimidine derivatives with a specific N-(3-pyridinylmethyl)urea moiety, 2-amino-4-(1-piperidine) pyridine derivatives, 7-azaindole and carboxamide derivatives and some others produced potential compounds. To overcome drug resistance, to get better affinity and to reduce drug toxicity, there is an urgent need for novel ALK inhibitors. The present review describes the ALK signaling, their inhibitors and related structure activity relationships for the development of potential ALK inhibitors.
Cancer is becoming a global threat as its treatment accounts for many challenges. Hence, newer inventions prioritize the requirement of developing novel anticancer agents. In this context, kinases ...have been exclusively investigated and developed as a promising and novel class of drug targets for anticancer regimen. Indole derivatives have been found to be most effective for targeting multiple kinases, such as PIM, CDK, TK, AKT, SRC, PI3K, PKD, GSK, etc., to inhibit cell proliferation for cancer. Recently, a group of researchers have proposed their research outcomes related to this moiety, such as Zhang et al. described some potent PI3K inhibitors by substitution at the 4th position of the indole ring. Kassis et al. enumerated several potent CDK5 inhibitors by substituting the 2nd and 6th positions of the indole ring. In the present review, we have taken the initiative to summarize structure-activity relationship (SAR) studies of indole derivatives as kinase inhibitors for the development of potential inhibitors.
PIK3CA gene was found in generation of p110 alpha (p110α) protein through an instruction process. p110 alpha acts as a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) proceed ...phosphorylation of signal molecules through PI3K pathway. This PI3K involved in regulation of cellular growth, transformation, adhesion, apoptosis, survival and motility. In some situations the PI3K/Akt pathway get altered due to mutation in PIK3CA gene produced oncogenic event in human malignancy.
The goal of this work is to describe the PI3K signaling pathway including mutational activation of PIK3CA gene and inhibitors have been developed or under clinical trials for the targeting of PI3K or PI3KR kinases.
Various inhibitors such as Morpholine, pyrimidines, benzenesulfonamide, pyridopyrimidinone, imidazo1,5naphthyridine, benzeneacylhydrazones, thienopyrimidine, aminopyridopyrimidine, imidazopyridine, imidazo1,2-apyridine, thiazolopyrimidinone, quinolines and quinoxalines, thieno3,2-bpyran-7-one, morpholino-1,3-benzoxazines, quinalozinones, pyrido 3,2-dpyrimidines, benzodthiazol-2-yl)acetamide, aminopyrimidines, chalcone , azaindole, pyrazolopyrimidine and pyridine, thienobenzoxepin, phenylquinazolines , pyrazolo1,5-apyridines , imidazolo-pyrimidine etc. were investigated under laboratory level as PI3K inhibitors in which few having PI3K and mTOR dual inhibitory activities.
After a long term of prognostic standpoint, PIK3CA mutations discussed as a major target for various cancers. These PIK3CA mutations were found in various exon including 1,2,4,6,7,9,13,18 and 20 which may be a cause of different cancers such as breast, colon, ovarian, gastric, brain, lung etc. In clinical trials these mutations still remain question marks for presence or absence to the scientist regarding future perspective. The opinion of these studies is to development of more specific inhibitors of PI3K pathway which produce tremendous impact on various cancers developed due to PIK3CA mutations.
