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Introduction: Fatty acid synthase (FASN), is a key metabolic enzyme involved in fatty acid biosynthesis and is an essential target for multiple disease progressions like cancer, obesity, NAFLD, etc. Aberrant expression of FASN is associated with deregulated energy metabolism of cells in these diseases. Area Covered: This article provides a summary of the most recent developments in the discovery of novel FASN inhibitors with potential therapeutic uses in cancer, obesity, and other metabolic disorders such as nonalcoholic fatty liver disease from 2016 to the present. The recently published patent applications and forthcoming clinical data of FASN inhibitors from both academia and the pharma industries are also highlighted in this study. Expert Opinion: The implication of FASN in multiple diseases has provided an impetus for developing novel inhibitors by both pharma companies and academia. Critical analysis of the patent literature reveals the exploration of diverse molecular scaffolds to identify potential FASN inhibitors that target the different catalytic domains of the enzyme. In spite of these multifaceted efforts, only one molecule, TVB-2640, has reached phase II trials for nonalcoholic steatohepatitis (NASH) and many malignancies. However, thecombined efforts of pharma companies to produce several FASN inhibitors might facilitate the clinical translation of this unique class of inhibitors. Nevertheless, concerted efforts towards developing multiple FASN inhibitors by pharma companies might facilitate the clinical translation of this novel class of inhibitors.

Fatty acid synthase (FASN) is one of the enzymes required for fatty acid biosynthesis and is expressed as low or absent in most normal cells/tissues. However, this enzyme is upregulated in various cancer cells; hence, it can act as an important target to design and develop novel FASN inhibitors for cancer therapy. In the present investigation, a series of structurally diverse compounds that possessed FASN inhibitory activities were subjected to classification analysis using different algorithms such as support vector machine, decision tree, Naïve Bayes and random forest. The physicochemical descriptors and MACCS fingerprints were calculated using PaDEL software, and the WEKA software was utilized for the classification model building. The statistical parameters/confusion matrix calculated from the analysis revealed that the selected models have significant predictive performances. The results showed that the topological properties of the molecules are the main determinant for the activity classification. The key descriptors comprised of hydrogen bonding groups, especially acceptor (nHBAcc, minHBint9, minHBint5 and nwHBa), charge on the topological surface of the molecules (JGI10GGI2), ionization potential (GATS5i and GATS1i) and branching and distance between the groups (ETA_Eta_B_RC) are significantly contributed in the classification models. Further, the presence of heteroatoms (MACCSFP82, MACCSFP93 and MACCSFP131), especially nitrogen atom(s) and hydrogen bond acceptor groups (N-N group, NC(=O)N, N-C(=O)), actively contributed to the inhibitory activities. The results concluded that the topological polar properties concentrated in a specific region have significant FASN inhibitory activity. Hence, these results shall be used to develop novel molecules with increased FASN inhibitory activity.

Abstract: Coronaviruses are a leading cause of emerging life-threatening diseases, as evidenced by the ongoing coronavirus disease pandemic (COVID-19). According to complete genome sequence analysis reports, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, has a sequence identity highly similar to the earlier severe acute respiratory syndrome coronavirus (SARSCoV). The SARS-CoV-2 has the same mode of transmission, replication, and pathogenicity as SARSCoV. The SARS-CoV-2 spike protein's receptor-binding domain (RBD) binds to host angiotensinconverting enzyme-2 (ACE2). The ACE2 is overexpressed in various cells, most prominently epithelial cells of the lung (surface of type 1 and 2 pneumocytes), intestine, liver, kidney, and nervous system. As a result, these organs are more vulnerable to SARS-CoV-2 infection. Furthermore, renin-angiotensin system (RAS) blockers, which are used to treat cardiovascular diseases, intensify ACE2 expression, leading to an increase in the risk of COVID-19. ACE2 hydrolyzes angiotensin- II (carboxypeptidase) to heptapeptide angiotensin (1-7) and releases a C-terminal amino acid. By blocking the interaction of spike protein with ACE2, the SARS-CoV-2 entry into the host cell and internalization can be avoided. The pathogenicity of SARS-CoV-2 could be reduced by preventing the RBD from attaching to ACE2-expressing cells. Therefore, inhibition or down-regulation of ACE2 in host cells represents a therapeutic strategy to fight against COVID-19. However, ACE2 plays an essential role in the physiological pathway, protecting against hypertension, heart failure, myocardial infarction, acute respiratory lung disease, and diabetes. Given the importance of ACE's homeostatic role, targeting of ACE2 should be realized with caution. Above all, focusing on the SARS-CoV-2 spike protein and the ACE2 gene in the host cell is an excellent way to avoid viral mutation and resistance. The current review summarises the sequence analysis, structure of coronavirus, ACE2, spike protein-ACE2 complex, essential structural characteristics of the spike protein RBD, and ACE2 targeted approaches for anti-coronaviral drug design and development.

Background : The discovery of novel antidiabetics for the treatment of type 2 diabetes mellitus (T2DM) is an important task nowadays because the current treatment approaches have certain limitations. The reported studies showed that the protein tyrosine phosphatase 1B (PTP1B) is a valuable target, can be used to develop significant antidiabetic molecules. Objective: In the present investigation, computational methods and biological evaluation studies have been applied to develop novel PTP1B inhibitors with good enzyme binding affinity and activity. Methods: Virtual screening (docking) analysis of SPECS database compounds on PTP1B enzyme was performed using Schrodinger software. In vitro and in vivo biological evaluations had been conducted with the identified hits. Results: The results revealed that the molecules identified through these studies have shown significant interactions with the active site residues of the PTP1B enzyme. The compounds S1 and S2 provided significant binding interactions with the residues (Arg221 and Gln262) and have shown considerable in vitro PTP1B inhibitory activity and in vivo antidiabetic activity. The compounds S1 and S2 possessed 35.44±0.12% and 33.68±0.08% inhibitory activities, respectively. Conclusion: These identified hits will be used as a template for design and development of novel PTP1B inhibitors with a compatible pharmacokinetic profile.

Prostate cancer (PC) is the most commonly diagnosed cancer in men. In PC, multiple molecular signaling networks are perturbed, so monotherapies are less effective, creating an urgent need to discover chemotherapeutic agents that target multiple tumor-promoting proteins simultaneously. Drug discovery research is increasingly embracing poly-pharmacology, in which one drug targets multiple oncogenic targets concurrently. We have identified a novel quinoline derivative, IND-2 (4-chloro-2-methylpyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinolone), that has been shown to significantly inhibit the expression of several oncogenic and epigenetic targets in PC cells. It was observed that IND-2 significantly inhibited the proliferation of PC-3 and DU-145 with IC50 values of 3 µM and 3.5 µM, respectively. Furthermore, 5 and 10 µM of IND-2 produced morphological changes in PC-3 cells characteristic of apoptosis. The levels of reactive oxygen species (ROS) increased significantly after IND-2 was added to PC cells. Additionally, 5 and 10 µM of IND-2 reduced mitochondrial membrane potential in PC-3 cells. Furthermore, IND-2 increased the expression of cleaved caspase-3, cleaved caspase-7, and cleaved poly (ADP-ribose) polymerase (PARP). The PC-3 cells incubated with 5 µM of IND-2 showed a significant reduction in expression of B-cell lymphoma 2 (Bcl-2). These data convincingly show that IND-2 inhibits PC cells through apoptosis induction. It is interesting to note that IND-2 (2.5, 5 and 10 µM) also induces mitotic catastrophe in PC-3 cells. Wound healing assay and expression of several EMT (epithelial to mesenchymal) markers indicated significant anti-metastatic activity of IND-2. Target identification studies have demonstrated that IND-2 mimics etoposide (VP-16) and binds more specifically to Topoisomerase IIβ. In our preliminary studies, we found that IND-2 inhibits several oncogenic and epigenetic targets including Topoisomerase II-Hsp90 complex and LSD1/HDAC1 of the transcriptional corepressor CoREST complex. However, these targets need to be validated to understand IND-2's mechanism. Overall, IND-2 may lead to the development of more effective poly-targeted compounds for PC treatment. Citation Format: Swapnaa Balaji, Rabin Neupane, Chandrabose Karthikeyan, Jayachandra Babu Ramapuram, Amit K. Tiwari. Development of novel pyrimido-pyrazolo-quinolone derivative, IND-2 as multi-targeted inhibitor for the treatment of prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4974.

A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC50 values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC50 of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.

Patients with advanced or metastatic colorectal cancer (CRC) often have poor prognosis and survival. There are ongoing efforts to identify novel molecules to manage advanced and metastatic CRC. Modifications in the quinazoline ring has resulted in effective and clinically approved drugs such as gefitinib, erlotinib, vandetanib among others. We rationalized and synthesized a series of 4-anilinoquinazoline analogues, DW (1-10) and evaluated them for anticancer efficacy in human CRC cell lines (HCT116, HT29, SW620). We identified a lead molecule DW-8, with sub-micromolar potency against CRC lines with selectivity index of DW-8 being >2 folds in CRC cells compared to non-cancerous line, CRL1459. Mechanistically, DW-8 produced significant morphological changes in SW620 cells. This included nuclear condensation, cell shrinkage, blebbing and apoptotic bodies formation which are the hallmarks of apoptosis. We found that the DW-8 induced apoptosis by i) producing cell cycle arrest at G2 phase; ii) activated intrinsic apoptosis as shown by cleaved caspases such as caspase-9, the executioner caspases 3 and 7; iii) produced nuclear fragmentation; and iv) increased the level of reactive oxygen species. We are now synthesizing the analogs of DW-8 and are optimizing the formulations for efficient delivery to CRC tumors in vivo. Overall, our result suggests DW-8 may represent a suitable lead for developing novel compound to treat CRC. Citation Format: Rabin Neupane, Saloni Malla, Mariam Sami Abou-Dahech, Swapnaa Balaji, Shikha Kumari, Yuan Tang, Chandrabose Karthikeyan, Amit K. Tiwari. Design and development of novel anticancer dimethoxyquinazoline-4-amine analog, DW-8, against colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5656.

A series of lH-pyrazolo[3,4-b]quinolin-3-amine derivatives were synthesized and evaluated for anticancer efficacy in a panel of ten cancer cell lines, including breast (MDAMB-231 and MCF-7), colon (HCT-116, HCT-15, HT-29 and LOVO), prostate (DU-145 and PC3), brain (LN-229), ovarian (A2780), and human embryonic kidney (HEK293) cells, a non-cancerous cell line. Among the eight derivatives screened, compound QTZ05 had the most potent and selective antitumor efficacy in the four colon cancer cell lines, with IC50 values ranging from 2.3 to 10.2 µM. Furthermore, QTZ05 inhibited colony formation in HCT-116 cells in a concentration-dependent manner. Cell cycle analysis data indicated that QTZ05 caused an arrest in the sub G1 cell cycle in HCT-116 cells. QTZ05 induced apoptosis in HCT-116 cells in a concentration-dependent manner that was characterized by chromatin condensation and increase in the fluorescence of fluorochrome-conjugated Annexin V. The findings from our study suggest that QTZ05 may be a valuable prototype for the development of chemotherapeutics targeting apoptotic pathways in colorectal cancer cells.

In this study, a series of 13 structural variants of thieno[2,3d]pyrimidine derivatives (6a-6m) were synthesized and screened for cytotoxicity in a panel of colorectal, ovarian, and brain cancer cell lines. The selectivity of the compounds was assessed by determining the cytotoxicity in normal epithelial cell line (CHO). The most potent compound, 6j, was efficacious (with IC50 range of 0.6-1.2 μM) in colon (HCT116 and HCT15), brain (LN-229 and GBM-10) and ovarian (A2780 and OV2008) cancer cell lines. In contrast, in the normal cell line (CHO), the IC50 values for 6j were 14 ± 1.3 μM. Compound 6j significantly inhibited the clonogenic potential of HCT116, OV2008 and A2780 cell lines in concentration - dependent (0.5-4 μM) manner. Also, 6j induced 1) formation of reactive oxygen species; 2) apoptosis and 3) mitotic catastrophe in HCT116 and OV2008 cells (IC50 = 0.5-2 μM). Furthermore, apoptosis was the predominant mechanism of death in A2780 cells. The cytotoxicity of 6j in wild type HCT116 cells was similar to that in HCT116 cells lacking the apoptotic genes for Bax, Bak, or Bak and Bax, indicating that 6j induces mitotic catastrophe as alternative mechanism of death when when certain apoptotic proteins are absent. In summary, this study has identified a lead molecule, 6j, that selectively induces oxidative stress, apoptosis and mitotic catastrophe in specific cancer (colon and ovarian) cell lines.

Agents targeting colchicine-binding pocket usually show a minimal drug-resistance issue, albeit often associated with high toxicity. Chalcone-based compounds, which may bind to colchicine-binding site, are found in many edible fruits, suggesting that they can be effective drugs with less toxicity. Therefore, we synthesized and examined 24 quinolone chalcone compounds, from which we identified ((E)-3-(3-(2-Methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR-17) and ((E)-6-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR-20) as promising leads. In particular, CTR-20 was effective against 65 different cancer cell lines originated from 12 different tissues, largely in a cancer cell-specific manner. We found that both CTR-17 and CTR-20 reversibly bind to the colchicine-binding pocket on β-tubulin. Interestingly however, both the CTRs were highly effective against multidrug-resistant cancer cells while colchicine, paclitaxel and vinblastine were not. Our study with CTR-20 showed that it overcomes multidrug-resistance through its ability to impede MRP1 function while maintaining strong inhibition against microtubule activity. Data from mice engrafted with the MDA-MB-231 triple-negative breast cancer cells showed that both CTR-17 and CTR-20 possess strong anticancer activity, alone or in combination with paclitaxel, without causing any notable side effects. Together, our data demonstrates that both the CTRs can be effective and safe drugs against many different cancers, especially against multidrug-resistant tumors.

Thienopyrimidines are a versatile group of compounds that contain a biologically active pharmacophore and reported to have anticancer efficacy in vitro. Here, we report for the first time, that thieno[3,2-d]pyrimidine - based compounds, designated the RP series, have efficacy in prostate cancer cells. The lead compound, RP-010, was efficacious in PC3 and DU-145 prostate cancer (PC) cells (IC50< 1µM). The cytotoxicity of RP-010 was significantly lower in normal cells. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in the G2 phase of the cell cycle, induced mitotic catastrophe and apoptotic signaling in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) inhibits the wingless-type MMTV (Wnt)/β-catenin signaling pathway, mainly by inducing β-catenin fragmentation, while down regulating important proteins in the pathway, i.e. LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced the nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the signaling pathway. In addition, RP-010 (0.5, 1, 2, and 4 µM) significantly decreased the migration and invasiveness of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations up to 6 µM. In conclusion, RP-10 is a promising anticancer compound in metastatic prostate cancer and did not produce overt toxicity in an in vivo zebrafish model. Future mechanistic and efficacy studies are needed in-vivo to optimize the lead compound RP-010 for clinical use.

// Xiaoyun Dai 1, * , Lingzhi Wang 1, 2, * , Amudha Deivasigamni 3, * , Chung Yeng Looi 4 , Chandrabose Karthikeyan 5 , Piyush Trivedi 5 , Arunachalam Chinnathambi 6 , Sulaiman Ali Alharbi 6 , Frank Arfuso 7 , Arunasalam Dharmarajan 7 , Boon Cher Goh 1, 2, 8 , Kam Man Hui 3, 9, 10, 11 , Alan Prem Kumar 1, 2, 12, 13 , Mohd Rais Mustafa 4 , Gautam Sethi 1, 6, 14 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2 Cancer Science Institute of Singapore, Centre for Translational Medicine, Singapore 3 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 4 Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia 5 School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, India 6 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia, 7 Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia 8 Department of Haematology-Oncology, National University Health System, Singapore 9 Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive Proteos, Singapore 10 Cancer and Stem Cell Biology Program, Duke–National University of Singapore Graduate Medical School, Singapore 11 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 12 Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth WA, Australia 13 Department of Biological Sciences, University of North Texas, Denton, Texas, USA 14 School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia * These authors contributed equally to this work Correspondence to: Gautam Sethi, email: phcgs@nus.edu.sg Kam Man Hui, email: cmrhkm@nccs.com.sg Mohd Rais Mustafa, email: rais@nm.edu.my Alan Prem Kumar, email: csiapk@nus.edu.sg Keywords: MBIC, HCC, JNK, ROS, apoptosis Received: July 27, 2016 Accepted: December 15, 2016 Published: January 12, 2017 ABSTRACT A prior screening programme carried out using MTT assay by our group identified a series of novel benzimidazole derivatives, among which Methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) showed highest anticancer efficacy compared to that of chemotherapeutic agent, cisplatin. In the present study, we found that MBIC inhibited cell viability in different hepatocellular carcinoma (HCC) cell lines without exerting significant cytotoxic effects on normal liver cells. Annexin V-FITC/PI flow cytometry analysis and Western blotting results indicated that MBIC can induce apoptosis in HCC cells, which was found to be mediated through mitochondria associated proteins ultimately leading to the activation of caspase-3. The exposure to MBIC also resulted in remarkable impairment of HCC cell migration and invasion. In addition, treatment with MBIC led to a rapid generation of reactive oxygen species (ROS) and substantial activation of c-Jun-N-terminal kinase (JNK). The depletion of ROS by N-Acetyl cysteine (NAC) partially blocked MBIC-induced apoptosis and JNK activation in HCC cells. Finally, MBIC significantly inhibited tumor growth at a dose of 25 mg/kg in an orthotopic HCC mouse model. Taken together, these results demonstrate that MBIC may inhibit cell proliferation via ROS-mediated activation of the JNK signaling cascade in HCC cells.

Overexpression of ATP-binding cassette transporter (ABC) subfamily G2 in cancer cells is known to elicit a MDR phenotype, ultimately resulting in cancer chemotherapy failure. Here, we report, for the first time, the effect of eight novel pyrimido[1″,2″:1,5]pyrazolo[3,4- b ]quinoline (IND) derivatives that inhibit ABCG2 transporter restoring cancer cell chemosensitivity. IND -4, -5, -6, -7, and -8, at 10 µM, and nilotinib at 5 µM, significantly potentiated (8–10 fold) the cytotoxicity of the ABCG2 substrates mitoxantrone (MX) and doxorubicin in HEK293 cells overexpressing ABCG2 transporter, MX (~14 fold) in MX-resistant NCI-H460/MX-20 small cell lung cancer, and of topotecan (~7 fold) in S1-M1-80 colon cancer cells which all stably expressing ABCG2. In contrast, cytotoxicity of cisplatin, which is not an ABCG2 substrate, was not altered. IND-5,-6,-7, and -8 significantly increased the accumulation of rhodamine-123 in multidrug resistant NCI-H460/MX-20 cells overexpressing ABCG2. Both IND-7 and -8, the most potent ABCG2 inhibitors, had the highest affinities for the binding sites of ABCG2 in modeling studies. In conclusion, the beneficial actions of new class of agents warrant further development as potential MDR reversal agents for clinical anticancer agents that suffer from ABCG2-mediated MDR insensitivity.

A novel series of 3-((2-chloroquinolin-3-yl)methylene)indolin-2-ones were synthesized, using the ‘molecular hybridization approach’ and evaluated for anticancer efficacy. Eleven 3-((2-chloroquinolin-3-yl)methylene)indolin-2-ones (LM01 to LM11) were synthesized and evaluated for in vitro cytotoxic efficacy in cancer (ovarian, prostate and colon) and two non-cancerous cell lines. Among the 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives, LM08, with a 6-Cl substitution in the 3-quinolinyl moiety, had selective and potent cytotoxic efficacy in the ovarian cancer cell line A2780. Further mechanistic investigations indicated that LM08 significantly inhibited the clonogenic survival of A2780 cancer cells, which was mediated by inducing apoptosis.

The inhibition of apoptosis, disruption of cellular microtubule dynamics, and over-activation of the epithelial mesenchymal transition (EMT), are involved in the progression, metastasis, and resistance of colorectal cancer (CRC) to chemotherapy. Therefore, the design of a molecule that can target these pathways could be an effective strategy to reverse CRC progression and metastasis. In this study, twelve novel silybin derivatives, HM015a-HM015k (15a−15k) and compound 17, were screened for cytotoxicity in CRC cell lines. Compounds HM015j and HM015k (15k and 15j) significantly decreased cell proliferation, inhibited colony formation, and produced cell cycle arrest in CRC cells. Furthermore, 15k significantly induced the formation of reactive oxygen species and apoptosis. It induced the cleavage of the intrinsic apoptotic protein (Bax p21) to its more efficacious fragment, p18. Compound 15k also inhibited tubulin expression and disrupted its structure. Compound 15k significantly decreased metastatic LOVO cell migration and invasion. Furthermore, 15k reversed mesenchymal morphology in HCT116 and LOVO cells. Additionally, 15k significantly inhibited the expression of the mesenchymal marker N-cadherin and upregulated the expression of the epithelial marker, E-cadherin. Compound 15k inhibited the expression of key proteins known to induce EMT (i.e., DVL3, β-catenin, c-Myc) and upregulated the anti-metastatic protein, cyclin B1. Overall, in vitro, 15k significantly inhibited CRC progression and metastasis by inhibiting apoptosis, tubulin activity and the EMT pathways. Overall, these data suggest that compound 15k should be tested in vivo in a CRC animal model for further development.

Described herein is the synthesis and biological evaluation of a series of non-carboxylic inhibitors of Protein Tyrosine Phosphatase 1B designed using bioisosteric replacement strategy. Six N-(3-(1H-tetrazol-5-yl)phenyl)acetamide derivatives designed employing the aforementioned strategy were synthesized and screened for PTP1B inhibitory activity. Among the synthesized compounds, compound NM-03 exhibited the most potent inhibitory activity with IC50 value of 4.48 µM. Docking studies with NM-03 revealed the key interactions with desired amino acids in the binding site of PTP1B. Furthermore, compound NM-03 also elicited good in vivo activity. Taken together, the results of this study establish N-(3-(1H-tetrazole-5-yl)phenyl)-2-(benzo[d]oxazol-2-ylthio)acetamide (NM-03) as a valuable lead molecule with great potential for PTP1B inhibitor development targeting diabetes.

Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/e (CK1δ/e) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line. Taken together, the results of this study establish N-(1H-pyrazol-3-yl)quinazolin-4-amines especially 3c and 3d as valuable lead molecules with great potential for CK1δ/e inhibitor development targeting neurodegenerative disorders and cancer.

The ATP - binding cassette (ABC) family G2 (ABCG2) transporters are known to produce multidrug resistance (MDR) in cancer, thereby limiting the clinical response to chemotherapy. Molecular modeling data indicated that certain dopamine (DA) D

The cdc2-like kinases (CLKs) are an evolutionarily conserved group of dual specificity kinases belonging to the CMGC (cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases). The CLK family consists of four isoforms namely CLK1, CLK2, CLK3 and CLK4. The human CLK1 encoded protein comprises 454 amino acids and the catalytic domain of CLK1 exhibits the typical protein kinase fold. CLK1 has been shown to autophosphorylate on serine, threonine and tyrosine residues and phosphorylate exogenous substrates on serine and threonine residues. CLK1 plays an important role in the regulation of RNA splicing through phosphorylation of members of the serine and arginine-rich (SR) family of splicing factors. CLK1 is involved in the pathophysiology of Alzheimer's disease by phosphorylating the serine residue in SR proteins. Nuclear speckles of the nucleoplasm contain the stored form of SR proteins and are moderately responsible for the choice of splicing sites during pre-mRNA splicing. Hence, the inhibition of CLK1 can be used as a therapeutic strategy for Alzheimer's disease. Many natural and synthetic molecules are reported to possess CLK1 inhibitory activity. Some specific examples are Marine alkaloid Leucettamine B and KH-CB19. Leucettamine B is a potent inhibitor of CLK1 (15 nM), Dyrk1A (40 nM), and Dyrk2 (35 nM) and a moderate inhibitor of CLK3 (4.5 µM) whereas KH-CB19 is a highly specific and potent inhibitor of the CLK1/CLK4. X-ray crystallographic studies have revealed the binding mode of marine sponge metabolite hymenialdisine and a dichloroindolyl enamino nitrile (KH-CB19) to CLK1. This review focuses on the role of CLKs in the pathophysiology of Alzheimer's disease and therapeutic potential of targeting CLK1 in Alzheimer's disease drug discovery and development. In addition, the recent developments in drug discovery efforts targeting human CLK1 are also highlighted.

Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC50 &lt, 1 &micro, M). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 &micro, M) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 &micro, M) affected the wingless-type MMTV (Wnt)/&beta, catenin signaling pathway, in association with &beta, catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 &micro, M) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 &micro, M) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 &micro, M. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use.

6H-Indolo[2,3-b]quinoxaline, a planar fused heterocyclic compound exhibits a wide variety of pharmacological activities. The mechanism of pharmacological action exerted by these compounds is predominantly DNA intercalation. The thermal stability of the intercalated complex (DNA and 6H-indolo[2,3-b]quinoxaline derivatives) is an important parameter for the elucidation of anticancer, antiviral and other activities. This thermal stability of the 6H-indolo[2,3- b]quinoxaline-DNA complex depends on the type of substituents and side chains attached to the 6H-indolo[2,3- b]quinoxaline nucleus and also the orientation of the side chain towards the GC rich minor groove of the DNA. Highly active 6H-indolo[2,3-b]quinoxaline derivatives such as NCA0424, B-220 and 9-OH-B-220 have shown good binding affinity to DNA as evident from high thermal stability of compound-DNA complex. Interestingly, these compounds possessed poor inhibitory activity on topoisomerase II enzyme but have significant MDR modulating activity. This review establishes '6H-indolo[2,3-b]quinoxaline' as a valuable template for design and development of novel molecules with different biological activities.