Mohane Selvaraj Coumar

Treat cancers by targeting survivin: Just a dream or future reality?

Since the discovery of survivin (BIRC5) as a cancer-related molecule by Grazia Ambrosini and Dario C. Altieri at 1997, our knowledge related to the function of this molecule has been extended from simple apoptosis inhibition to complicated, interlinked processes that involve interference of mitosis, apoptosis, autophagy, and even DNA repair recently. However, despite the growing amount of knowledge related to survivin in the last ten years, the development of survivin inhibitors or survivin-related molecular therapies is surprisingly and relatively slow as compared to other therapeutic inhibitors for cancer treatment. Here, the molecular functions of survivin and the progress of development of survivin-targeting therapies are discussed in detail. Functional differences between different survivin-specific inhibitors are discussed from both structural and biochemical point of views. This review also reveals different challenges that scientists are currently facing in the development of survivin inhibitors for clinical application. Finally, future directions for the development of survivin-targeted therapies are discussed in this review.

Anti-Influenza Drug Discovery: Structure-Activity Relationship and Mechanistic Insight into Novel Angelicin Derivatives

By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

Design and Synthesis of Tetrahydropyridothieno[2,3-d]pyrimidine Scaffold Based Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors: The Role of Side Chain Chirality and Michael Acceptor Group for Maximal Potency

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

Structure-based drug design of novel Aurora kinase A inhibitors: structural basis for potency and specificity.

Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure-based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC(50) = 15.1 microM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetamidophenyl ring led to the identification of 12w with a approximately 450-fold improved Aurora kinase A inhibition potency (IC(50) = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.

Aurora kinase inhibitor patents and agents in clinical testing: an update (2011 – 2013)

Introduction: Aurora kinase A, B and C, members of serine/threonine kinase family, are key regulators of mitosis. As Aurora kinases are overexpressed in many of the human cancers, small-molecule inhibitors of Aurora kinase have emerged as a possible treatment option for cancer. Areas covered: In 2009 and 2011, the literature pertaining to Aurora kinase inhibitors and their patents was reviewed. Here, the aim is to update the information for Aurora kinase inhibitors in clinical trials and the patents filed between the years 2011 and 2013. Pubmed, Scopus®, Scifinder®, USPTO, EPO and www.clinicaltrials.gov databases were used for searching the literature and patents for Aurora kinase inhibitors. Expert opinion: Even though both Aurora sub-type selective as well as pan-selective inhibitors show preclinical and clinical efficacy, so far no Aurora kinase inhibitor has been approved for clinical use. Particularly, dose-limiting toxicity (neutropenia) is a key issue that needs to be addressed. Preliminary evidence suggests that the use of selective Aurora A inhibitors could avoid Aurora B-mediated neutropenia in clinical settings. Also, use of adjunctive agents such as granulocyte stimulating factor to overcome neutropenia associated with Aurora B inhibition could be an answer to overcome the toxicity and bring Aurora inhibitors to market in the future.

Scaffold-hopping strategy: Synthesis and biological evaluation of 5,6-fused bicyclic heteroaromatics to identify orally bioavailable anticancer agents

Utilizing scaffold-hopping drug-design strategy, we sought to identify a backup drug candidate for BPR0L075 (1), an indole-based anticancer agent. For this purpose, 5,6-fused bicyclic heteroaromatic scaffolds were designed and synthesized through shuffling of the nitrogen from the N-1 position or by insertion of one or two nitrogen atoms into the indole core of 1. Among these, 7-azaindole core 12 showed potent in vitro anticancer activity and improved oral bioavailability (F = 35%) compared with 1 (F < 10%).

Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead Identification

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.

Generation of Ligand-Based Pharmacophore Model and Virtual Screening for Identification of Novel Tubulin Inhibitors with Potent Anticancer Activity

A pharmacophore model, Hypo1, was built on the basis of 21 training-set indole compounds with varying levels of antiproliferative activity. Hypo1 possessed important chemical features required for the inhibitors and demonstrated good predictive ability for biological activity, with high correlation coefficients of 0.96 and 0.89 for the training-set and test-set compounds, respectively. Further utilization of the Hypo1 pharmacophore model to screen chemical database in silico led to the identification of four compounds with antiproliferative activity. Among these four compounds, 43 showed potent antiproliferative activity against various cancer cell lines with the strongest inhibition on the proliferation of KB cells (IC(50) = 187 nM). Further biological characterization revealed that 43 effectively inhibited tubulin polymerization and significantly induced cell cycle arrest in G(2)-M phase. In addition, 43 also showed the in vivo-like anticancer effects. To our knowledge, 43 is the most potent antiproliferative compound with antitubulin activity discovered by computer-aided drug design. The chemical novelty of 43 and its anticancer activities make this compound worthy of further lead optimization.

Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors

The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.

Aurora kinase inhibitor patents and agents in clinical testing: an update (2009 – 10): This article is an update to aurora kinase inhibitors review, which appeared in: Expert Opin. Ther. Patents 2009, 19, 1-36 and Expert Opin. Investig. Drugs 2009, 18, 1-20.

Introduction: Mitosis is a key step in the cell cycle and is controlled by several cell cycle regulators, including aurora kinases. Aurora family members A, B and C are essential for spindle assembly, centrosome maturation, chromosomal segregation and cytokinesis. Overexpression/amplification of aurora kinases has been implicated in oncogenic transformation, including the development of chromosomal instability in cancer cells. Hence, the use of aurora kinase small molecule inhibitors as a potential molecular-targeted therapeutic intervention for cancer is being pursued by various researchers. Area covered: This review provides an update on aurora kinase inhibitors based on developments from 2009 to 2010. The medicinal chemistry aspects of aurora kinase inhibitors, with a particular emphasis on the patent literature, are reviewed. Databases such as PubMed, SCOPUS, Scifinder and www.clinicaltrials.gov database were used to search for literature in the preparation of this review. Expert opinion: Around a dozen aurora kinase inhibitors are currently undergoing various Phase I – II evaluations for different human cancers. Instead of being applied as a monotherapy, combinations of aurora kinase inhibitors and existing chemotherapeutic compounds seem to give better therapeutic outcomes and are, therefore, a promising future cancer therapy.