Kinase Inhibitory Activity Research Articles

Abstract P42: Beyond the Canonical: uORF-encoded Micro Peptides as Novel Kinase Inhibitors in Cancer Therapy

Abstract About 40% of human mRNAs contain upstream open reading frames (uORFs) in their 5’-untranslated regions. Some of these uORF sequences thought to attenuate scanning ribosomes or lead to mRNA degradation were recently shown to be translated, although the function of most encoded peptides remains unknown. Our recent study was the first to reveal a uORF-encoded peptide exhibiting kinase inhibitory activity (Jayaram DR, et al. PNAS (2021)). This uORF (uORF2), upstream of a protein kinase C (PKC) family member (PKCeta) main ORF, encodes for a peptide (uPEP2) containing the typical PKC pseudosubstrate (PS) motif present in all PKCs that auto-inhibits their kinase activity. We show direct binding and selective inhibition of the catalytic activity of novel PKCs by uPEP2 (but not of classical or atypical PKCs). Functionally, treatment of breast cancer cells with uPEP2 diminished cell survival and their migration and synergized with chemotherapy by interfering with the response to DNA damage. Furthermore, in a xenograft of MDA-MB-231 triple-negative breast cancer in mice models, uPEP2 suppressed tumor progression, invasion, and metastasis. The endogenous deletion of uORF2 by CRISPR/Cas9 in the non-tumorigenic MCF-7 cells showed that it impedes cell proliferation, acting as a growth suppressor. Its role in tumor formation and metastasis is presently studied in breast cancer models with metastasis to the lungs. Together, we point to a new layer of protein regulation by a uORF-encoded kinase inhibitor, which could present a forerunner for other uORFs, possessing kinase inhibitory function. Notably, we have recently identified an additional uORF with a PS motif upstream of another PKC. As kinase inhibitors, uORF-encoded peptides may play a role in signaling and stress, acting in cis and/or in trans, forming diverse regulatory networks, thereby opening new views into eukaryotic protein regulation and cancer biology. Citation Format: Divya Ram Jayaram, Sigal Frost, Chanan Argov, Vijayasteltar Belsamma Liju, Nikhil Ponnoor Anto, Amitha Muraleedharan, Assaf Ben-Ari, Rose Sinay, Ilan Smoly, Ofra Novoplansky, Noah Isakov, Debra Toiber, Chen Keasar, Moshe Elkabets, Esti Yeger-Lotem, Etta Livneh. Beyond the Canonical: uORF-encoded Micro Peptides as Novel Kinase Inhibitors in Cancer Therapy [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P42.

Design, synthesis, biological assessment and molecular modeling studies of novel imidazothiazole-thiazolidinone hybrids as potential anticancer and anti-inflammatory agents

A new series of imidazothiazole derivatives bearing thiazolidinone moiety (4a-g and 5a-d) were designed, synthesized and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer and anti-inflammatory activity, cardiomyopathy toxicity and hepatotoxicity. Compound 4c inhibited EGFR kinase at a concentration of 18.35 ± 1.25 µM, whereas standard drug erlotinib showed IC50 value of 06.12 ± 0.92 µM. The molecular docking, dynamics simulation and MM-GBSA binding energy calculations revealed strong interaction of compound 4c with binding site of EGFR. The synthesized compounds were evaluated for their anticancer activity by MTT assay against three human cancer cell lines A549 (Lung), MCF-7 (Breast), HCT116 (Colon), one normal human embryonic kidney cell line HEK293 and also for their EGFR kinase inhibitory activity. Few compounds of the series (4a, 4b, 4c) showed promising growth inhibition against all the tested cancer cell lines and against EGFR kinase. Among these, compound 4c was found to be most active and displayed IC50 value of 10.74 ± 0.40, 18.73 ± 0.88 against cancer cell lines A549 and MCF7 respectively whereas it showed an IC50 value of 96.38 ± 1.79 against HEK293 cell line indicating lesser cytotoxicity for healthy cell. Compounds 4a, 4b and 4c were also examined for their apoptosis inducing potential through AO/EB dual staining assay and it was observed that their antiproliferative activity against A549 cells is mediated via induction of apoptosis. Cardiomyopathy studies showed normal cardiomyocytes with no marked sign of pyknotic nucleus of compounds 4b and 4c. Hepatotoxicity studies of compounds 4b and 4c also showed normal architecture of hepatocytes. Compounds 4a-g and 5a-d were also evaluated for their in-vitro anti-inflammatory activity by protein albumin denaturation assay. Among the tested compounds 4a-d and 5a-b showed promising activity and were selected for in-vivo inflammatory activity against carrageenan rat paw edema test. Among these compounds, 4b was found to be most active in the series showing 84.94% inhibition, whereas the standard drug diclofenac sodium showed 84.57% inhibition. Compound 4b also showed low ulcerogenic potential and lipid peroxidation. Thus, compounds 4c and 4b could be a promising lead compounds for developing anticancer and anti-inflammatory agents with low toxicity and selectivity.

ROCK Kinase Inhibitory Activity of Some Isoflavonoids and Their Pharmacological Significance in Glaucoma

ROCK Kinase Inhibitory Activity of Some Isoflavonoids and Their Pharmacological Significance in Glaucoma

Abstract 4474: Novel analogs of 4-substituted pyrrolo[2,3-d]pyrimidines as dual-targeted mEGFR/AURKA inhibitors for lung cancer

Abstract Small molecule, mutant epidermal growth factor receptor kinase (mEGFR) inhibitors such as osimertinib and erlotinib constitute the recommended therapy for mEGFR-positive non-small cell lung cancer (NSCLC). However, mEGFR inhibitors are ineffective in NSCLC over time due to mutations within mEGFR and redundant signaling pathways such as mutant KRAS (mKRAS) that bypass mEGFR inhibition. Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on tumor growth inhibition and tumor resistance. Studies have shown that resistance to mEGFR inhibitors was overcome when mEGFR inhibitors were combined with aurora kinase (AURK) inhibitors. Additionally, mEGFR inhibitors were found to retain their anticancer effects in mKRAS-positive NSCLC cells if given concurrently with AURK inhibitors. Kurup et al. previously reported a series of 4-substituted pyrrolo[2,3-d]pyrimidines as dual mEGFR/AURKB inhibitors. Novel analogs of 1-5 have been designed to incorporate AURKA inhibition while maintaining mEGFR inhibition. Molecular modeling was utilized to guide selectivity for AURKA over AURKB. This study led to the identification of novel dual-targeted mEGFR/AURKA inhibitors with demonstrated inhibition of mKRAS+ NSCLC and mEGFR+ NSCLC. The design, synthesis, kinase inhibitory activities, and anticancer effects for these novel analogs will be presented. Structure-activity relationships for dual mEGFR/AURKA inhibition will be defined. Citation Format: Sonali Kurup, Gabe Carpenter, Samantha Satawa, Felix Amissah, Erika Lisabeth, Matthew Giletto, Edmund Ellsworth. Novel analogs of 4-substituted pyrrolo[2,3-d]pyrimidines as dual-targeted mEGFR/AURKA inhibitors for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4474.

Abstract 4617: Fisetin, a multi-kinase inhibitor enhances chemotherapeutic sensitivity in head and neck cancer

Abstract Background: The limitations of chemotherapeutic applications are often imposed by dose-related toxicity and the emergence of therapeutic resistance. Fisetin, a naturally occurring flavonoid, has demonstrated anticancer properties in various cancer types. Despite its proven effectiveness against cancer, the molecular target of fisetin remains unknown. Methods: Our study focused on understanding how fisetin and chemotherapy work together to inhibit the growth and survival of human HNC. We conducted in silico, in vitro and in vivo investigations. We employed target prediction, kinase profiling, transcriptome analysis and tumor xenograft to identify the chemosensitivity efficacy and mechanism of fisetin. Results: In-silico target prediction suggested that fisetin might target multiple kinases. Based on this lead, we have screened fisetin for different kinase inhibition activities and found that it inhibits multiple CDKs including CDK1, 2, 4, 5 and 6 at nanomolar concentration. To test its cellular activity, we have selected the head and neck cancer (HNC) model and found that fisetin treatment strongly inhibited cell proliferation and arrested the HNC cells in G1 phase followed by apoptotic cell death. In tumor xenograft experiment, we found that oral fisetin treatment inhibited the FaDu and SAS tumor growth in the athymic mouse model. Transcriptome analysis on FaDu and SAS cell lines indicated that fisetin treatment significantly modulates pathways associated with cell cycle progression and regulation. These pathways include cellular assembly, DNA replication, cell death, and cell morphology. Pretreatment of HNC cells with fisetin improved the effectiveness of chemotherapy drugs including cisplatin, 5-fluorouracil, and docetaxel. Consistent with this, fisetin pre-treated cells showed elevated levels of cellular and mitochondrial ROS followed by the activation of caspases and apoptosis induction when compared with that in control cells after cisplatin, 5-FU, or docetaxel treatment. Conclusion: These results imply that fisetin has the potential to be utilized as a multi-kinase inhibitor in cancer cells. The study revealed that fisetin has a strong potential for increasing the sensitivity of cancer cells to chemotherapy. Citation Format: Dhanir Tailor, Deepali Mishra, Sanjay V. Malhotra, Rana P. Singh. Fisetin, a multi-kinase inhibitor enhances chemotherapeutic sensitivity in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4617.

Synthesis, kinase inhibition and anti-leukemic activities of diversely substituted indolopyrazolocarbazoles

Pyrazole analogues of the staurosporine aglycone K252c, in which the lactam ring was replaced by a pyrazole moiety, were synthesized. In this series, one or the other nitrogen atoms of the indolocarbazole scaffold was substituted by aminoalkyl chains, aiming at improving protein kinase inhibition as well as cellular potency toward acute myeloid leukemia (AML) cell lines. Compound 19a, substituted at the N12-position by a 3-(methylamino)propyl group, showed high cellular activity in the low micromolar range toward three AML cell lines (MOLM-13, OCI-AML3 and MV4-11) with selectivity over non-cancerous cells (NRK, H9c2). 19a is also a highly potent inhibitor of the three Pim kinase isoforms, Pim-3 being the most inhibited with an IC50 value in the nanomolar range. A selectivity screening toward a panel of 50 protein kinases showed that 19a also potently inhibited PRK2 and to a lower extent AMPK, MARK3, GSK3β and JAK3. Our results enhance the understanding of the structural characteristics of indolopyrazolocarbazoles essential for potent protein kinase inhibition with therapeutic potential against AML.

A Compact Reprogrammed Genetic Code for De Novo Discovery of Proteolytically Stable Thiopeptides.

Thiopeptides make up a group of structurally complex peptidic natural products holding promise in bioengineering applications. The previously established thiopeptide/mRNA display platform enables de novo discovery of natural product-like thiopeptides with designed bioactivities. However, in contrast to natural thiopeptides, the discovered structures are composed predominantly of proteinogenic amino acids, which results in low metabolic stability in many cases. Here, we redevelop the platform and demonstrate that the utilization of compact reprogrammed genetic codes in mRNA display libraries can lead to the discovery of thiopeptides predominantly composed of nonproteinogenic structural elements. We demonstrate the feasibility of our designs by conducting affinity selections against Traf2- and NCK-interacting kinase (TNIK). The experiment identified a series of thiopeptides with high affinity to the target protein (the best KD = 2.1 nM) and kinase inhibitory activity (the best IC50 = 0.15 μM). The discovered compounds, which bore as many as 15 nonproteinogenic amino acids in an 18-residue macrocycle, demonstrated high metabolic stability in human serum with a half-life of up to 99 h. An X-ray cocrystal structure of TNIK in complex with a discovered thiopeptide revealed how nonproteinogenic building blocks facilitate the target engagement and orchestrate the folding of the thiopeptide into a noncanonical conformation. Altogether, the established platform takes a step toward the discovery of thiopeptides with high metabolic stability for early drug discovery applications.

Insights into the Overcoming EGFRDel19/T790M/C797S Mutation: A Perspective on the 2-Aryl-4-aminothienopyrimidine Backbone.

The epithelial growth factor receptor (EGFR) signaling pathway has been proposed to benefit non-small cell lung cancer (NSCLC) treatment. In this manuscript, we investigated the modification of 2-aryl-4-aminoquinazoline, the classical backbone of the fourth-generation EGFR inhibitors, in addition to obtaining a series of novel 2-aryl-4-aminothienopyrimidine derivatives (A1~A45), we also gained further understanding of the modification of this framework. Derivatives were tested for cytotoxicity against cancer cell lines (cervical cancer cell line Hela, lung cancer cell lines A549, H1975, and PC-9, Ba/F3-EGFRDel19/T790M/C797S cells, and human normal hepatocytes LO2) as well as for the derivative's inhibitory activity against EGFRWT, EGFRL858R/T790M, and EGFRDel19/T790M/C797S kinase inhibitory activities. The results showed that most of the target compounds showed moderate to excellent activity against one or more cancer cell lines. Among them, the antitumor activity (IC50) of the most promising A9 against A549 and H1975 cell lines was 0.77±0.08 μM, 6.90±0.83 μM, respectively. At concentration of 10 μM, A9 can be employed as the fourth-generation of EGFR inhibitors with the ability to overcome the C797S drug resistance since it can suppress EGFRDel19/T790M/C797S cells and kinase by 98.90 % and 85.88 %, respectively. Moreover, the tumor-bearing nude mice experiment further shows that A9 can significantly inhibit the growth of tumor in vivo, with the tumor inhibition rate (TIR) of 55.92 %, which was equivalent to the positive group. After that, from the result of HE staining experiment and blood biochemical analysis experiment, A9 show low toxicity and good safety, which is worthy of further research and development.

Chemical profiling and arginine kinase inhibitory activity of Angelica dahurica leaves

Angelica dahurica is a medicinal herb of the Umbelliferae family. The dried root of A. dahurica, also known as Angelicae dahuricae Radix, is widely used in clinical treatment. However, the aboveground part of A. dahurica which accounted for over 70% of the total plant was abandoned in the field. In order to develop the value of the aboveground part of A. dahurica, the chemical constituents and arginine kinase (AK) inhibitory activity of A. dahurica leaves were studied. 85 volatile components were identified from A. dahurica leaves by GC-MS; 39 non-volatile components including sugars, amino acids and organic acids were identified by pre-column derivatization GC-MS analysis; and 7 coumarins were qualitatively and quantitatively analyzed by HPLC. Then, an inhibitory enzyme-linked immunosorbent assay (iEIA) was applied for evaluation of AK inhibitory activity. The extracts of A. dahurica leaves exhibited well inhibitory effects on AK. Further, potential AK inhibitors were screened by grey relational analysis and their inhibitory activities were validated by iEIA. l-aspartic acid exhibited strongest inhibitory effect on AK with its IC50 value was 0.558 mM, which was much lower than that of chlorpheniramine (6.644 mM). The obtained chemical profiles displayed chemical diversity of A. dahurica leaves and will provide data support for the future development and utilization of A. dahurica leaves. The screened potential AK inhibitors from A. dahurica leaves could be candidates for development of antiallergic substances or insecticides.

Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer

Traf2-and Nck-interacting protein kinase (TNIK) plays an important role in regulating signal transduction of the Wnt/β-catenin pathway and is considered an important target for the treatment of colorectal cancer. Inhibiting TNIK has potential to block abnormal Wnt/β-catenin signal transduction caused by colorectal cancer mutations. We discovered a series of 6-(1-methyl-1H-imidazole-5-yl) quinoline derivatives as TNIK inhibitors through Deep Fragment Growth and virtual screening. Among them, 35b exhibited excellent TNIK kinase and HCT116 cell inhibitory activity with IC50 values of 6 nM and 2.11 μM, respectively. 35b also shown excellent kinase selectivity, PK profiles, and oral bioavailability (84.64%). At a p. o. dosage of 50 mg/kg twice daily 35b suppressed tumor growth on the HCT116 xenograft model. Taken together, 35b is a promising lead compound of TNIK inhibitors, which merits further investigation.

Novel sulfonamide-indolinone hybrids targeting mitochondrial respiration of breast cancer cells

Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options via targeted therapy. Beside kinases’ aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach to tackle BC. Based on a previously reported indolinone-based Aurora B kinase inhibitor (III), and guided by structural modification and SAR investigation, we initially synthesized 11 sulfonamide-indolinone hybrids (5a-k), which showed differential antiproliferative activities against the NCI-60 cell line panel with BC cells displaying preferential sensitivity. Nonetheless, modest activity against Aurora B kinase (18–49% inhibition) was noted at 100 nM. Screening of a representative derivative (5d) against 17 kinases, which are overexpressed in BC, failed to show significant activity at 1 μM concentration, suggesting that kinase inhibitory activity only played a partial role in targeting BC. Bioinformatic analyses of genome-wide transcriptomics (RNA-sequencing), metabolomics, and CRISPR loss-of-function screens datasets suggested that indolinone-completely responsive BC cell lines (MCF7, MDA-MB-468, and T-47D) were more dependent on mitochondrial oxidative phosphorylation (OXPHOS) compared to partially responsive BC cell lines (MDA-MB-231, BT-549, and HS 578 T). An optimized derivative, TC11, obtained by molecular hybridization of 5d with sunitinib polar tail, manifested superior antiproliferative activity and was used for further investigations. Indeed, TC11 significantly reduced/impaired the mitochondrial respiration, as well as mitochondria-dependent ROS production of MCF7 cells. Furthermore, TC11 induced G0/G1 cell cycle arrest and apoptosis of MCF7 BC cells. Notably, anticancer doses of TC11 did not elicit cytotoxic effects on normal cardiomyoblasts and hepatocytes. Altogether, these findings emphasize the therapeutic potential of targeting the metabolic vulnerability of OXPHOS-dependent BC cells using TC11 and its related sulfonamide-indolinone hybrids. Further investigation is warranted to identify their precise/exact molecular target.

Design, synthesis, and antiproliferative activities of novel substitutedhydrazone/triazolo-linked quinazoline derivatives

A series of novel hydrazonoquinazolines and triazoloquinazolines analogues of Erlotinib were synthesized and evaluated for their antiproliferative as well as EGFR kinase inhibitory activities. Most of the quinazoline compounds showed significant antiproliferative against different cancer cells. Among these, both compounds 4b and 5b were the best members of all the tested cancer cell lines with IC50 in the range 1.25–4.92 μM and 1.95–7.60 μM, respectively (c.f. erlotinib (IC50 7.52–16.02 μM) and inhibited EGFR with IC50 0.80 and 0.66 μM, sequentially. Additionally, these two compounds effectively induced cell cycle arrest and triggered apoptosis in HL-60 cancer cells by regulating the pro-apoptotic protein BAX and anti-apoptotic protein Bcl-2 expression. The docking studies revealed that there are interactions like that of erlotinib at the EGFR active site. In conclusion, the synthesized quinazoline compounds 4b and 5b effectively inhibit EGFR. Such a finding can be sited as a good starting point for the development of novel antitumor compounds targeting EGFR kinase.

Synthesis of novel [1,2,3]triazolo[4′,5′:3,4]pyrrolo[1,2‐a]thieno[2,3‐d] pyrimidines: Potent EGFR targeting anti‐breast cancer agents

AbstractIn this study, we designed and synthesized several novel fused [1,2,3]triazolo [4′,5′:3,4]pyrrolo[1,2‐a]thieno[2,3‐d]pyrimidine derivatives using in a single [3 + 2] reaction cycloaddition reaction of 3‐(3‐iodoprop‐2‐yn‐1‐yl)thieno[2,3‐d]pyrimidin‐4(3H)‐one (4) followed by C‐C bond coupling with various aryl azides in a PEG‐400 medium. All of the newly synthesized compounds were evaluated in vitro for EGFR kinase inhibitory action as well as anti‐breast cancer activity against MDA‐MB‐231 and MCF‐7 breast cancer cell lines. When compared to the reference molecule, erlotinib, the majority of the compounds demonstrated adequate efficacy. The most promising compounds, 5g and 5i, demonstrated excellent anticancer activity against both cancer cell lines, with IC50 values ranging from 04.17 ± 0.55 to 8.65 ± 0.89 μM, respectively, as well as excellent kinase inhibitory activities (EGFR: IC50 = 0.467 ± 0.063 and 0.412 ± 0.081 μM). The in silico studies of five potent compounds 5f, 5g, 5h, 5i, and 5k were also carried out to identify the interactions against the EGFR receptor and found that the energy calculations were covenant with the obtained IC50 values.

Small-Molecule-Directed Endogenous Regeneration of Visual Function in a Mammalian Retinal Degeneration Model.

Degenerative retinal diseases associated with photoreceptor loss are a leading cause of visual impairment worldwide, with limited treatment options. Phenotypic profiling coupled with medicinal chemistry were used to develop a small molecule with proliferative effects on retinal stem/progenitor cells, as assessed in vitro in a neurosphere assay and in vivo by measuring Msx1-positive ciliary body cell proliferation. The compound was identified as having kinase inhibitory activity and was subjected to cellular pathway analysis in non-retinal human primary cell systems. When tested in a disease-relevant murine model of adult retinal degeneration (MNU-induced retinal degeneration), we observed that four repeat intravitreal injections of the compound improved the thickness of the outer nuclear layer along with the regeneration of the visual function, as measured with ERG, visual acuity, and contrast sensitivity tests. This serves as a proof of concept for the use of a small molecule to promote endogenous regeneration in the eye.

Design, Synthesis, in vitro Anti‐inflammatory Activity and in silico Studies of Imidazole‐Based 1,2,3‐Triazole Hybrids Targeting p38 MAP Kinase

Abstractp38 MAP kinases are involved in numerous inflammatory diseases. A series of 14 molecules of 1,2,3 triazole linked 4‐((2‐cyclohexyl‐4,5‐diphenyl‐1H‐imidazol‐1‐yl) methyl)‐1‐phenyl hybrids(7 a–7 n) has been synthesized by click reaction. Spectral data characterized all the synthesized compounds. The final compounds were screened for in vitro p38 MAP kinase inhibitory activity. Three compounds from the series 7 c, 7 f, and 7 n expounded superior activity with IC50 values 234.08±19.65 nM, 222.68±20.69 nM, and 241.70±20.51 nM respectively while two compounds (7 d and 7 e) showed considerable activity compared to prototype drug Adezmapimod (SB203580) (IC50 value 257.13±23.94 nM). The docking study of synthesized molecules revealed that the three compounds (7 f,7 g, and 7 n) showed higher binding affinities than Adezmapimod. The “Desmond v3.6 Program” was utilized to conduct MD simulations. The result revealed that compound 7 f was conformationally stable. The ADME studies were performed using the Swiss ADME algorithm. Studies revealed that all the compound‘s defiance of Lipinski's rule is within acceptable ranges with few violations. Compound 7 f was orally active and showed good gastrointestinal absorption within the acceptable range. The search for newer compounds with increased activity compared to Adezmapimod resulted in identifying a novel subclass of p38 MAP kinase inhibitors.

Exploring the untapped pharmacological potential of imidazopyridazines.

Imidazopyridazines are fused heterocycles, like purines, with a pyridazine ring replacing the pyrimidine ring in purines. Imidazopyridazines have been primarily studied for their kinase inhibition activity in the development of new anticancer and antimalarial agents. In addition to this, they have also been investigated for their anticonvulsant, antiallergic, antihistamine, antiviral, and antitubercular properties. Herein, we review the background and development of different imidazopyridazines as potential pharmacological agents. Moreover, the scope of this relatively less charted heterocyclic scaffold is also highlighted.

Comparative Protein Kinase inhibitory activity of three Acacia species growing in Nigeria

Comparative Protein Kinase inhibitory activity of three Acacia species growing in Nigeria

Imparting aromaticity to 2-pyridone derivatives by O-alkylation resulted in new competitive and non-competitive PIM-1 kinase inhibitors with caspase-activated apoptosis

New aromatic O-alkyl pyridine derivatives were designed and synthesised as Proviral Integration Moloney (PIM)-1 kinase inhibitors. 4c and 4f showed potent in vitro anticancer activity against NFS-60, HepG-2, PC-3, and Caco-2 cell lines and low toxicity against normal human lung fibroblast Wi-38 cell line. Moreover, 4c and 4f induced apoptosis in the four tested cancer cell lines with high percentage. In addition, 4c and 4f significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 4c and 4f showed potent PIM-1 kinase inhibitory activity with IC50 = 0.110, 0.095 µM, respectively. Kinetic studies indicated that 4c and 4f were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, in silico prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that 4c and 4f could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties.

S-Alkylated quinazolin-4(3H)-ones as dual EGFR/VEGFR-2 kinases inhibitors: design, synthesis, anticancer evaluation and docking study.

Dual targeting by a single molecule has emerged as a promising strategy for fighting cancer. In this study, a new set of 2-thioquinazolin-4(3H)-ones as potential anti-cancer surrogates endowed with dual EGFR/VEGFR-2 kinases inhibitory activities were synthesized. The anti-tumor potency of the newly synthesized candidates 4-27 was evaluated against a panel of four cancer cell lines. The prepared candidates 4-27 showed comparable activity to that of the standard drug sorafenib. For instance, compound 4 (IC50 = 1.50-5.86 μM) and compound 20 (IC50 = 4.42-6.39 μM) displayed superior potencies against all cell lines compared to sorafenib (IC50 = 5.47-7.26 μM). Dual EGFR/VEGFR-2 inhibitory activities of the most active analogues (4, 11, and 20) were investigated. Compound 4 showed comparable EGFR/VEGFR-2 inhibitory activity to the used control drugs. Flow cytometric analysis indicates that the most potent analogue 4 stopped the cell cycle at the G1 phase and induced 46.53% total apoptosis in HCT-116 cells that was much more powerful than the untreated cells with 2.15% apoptosis. Molecular docking and dynamic simulations of 4, 11, and 20 with EGFR and VEGFR-2 were performed to examine the binding mode and interaction within the enzyme binding pockets.

Synthetic and Pharmacological Expedition of Pyrazolo[1,5-a]pyridine: A Comprehensive Review

Abstract: Fused nitrogen-containing heterocyclic compounds have been identified to display a prominent role in medicinal chemistry, biochemistry, and other streams of science. Countless derivatives of pyrazolo[ 1,5-a] pyridine have been investigated by researchers for their distinct pharmacological characterization. In this article, we have revealed and arranged the various routes of synthesis and therapeutic activities such as dopamine binding affinity, kinase inhibitory activity, and PDE inhibitors of pyrazolo[1,5- a]pyridine-containing compounds which have been explored till now. The remarkable outcomes obtained via in vitro as well as in vivo profile screening of this moiety and its derivatives lead this scaffold to be recognized to a greater extent and examined further for better results. This review will give medicinal chemists a flying-bird eye catch view of pyrazolo[1,5-a] pyridine derivatives which will help them to design and synthesize potential compounds bearing this moiety.