Pankaj Kumar Singh

Novel EGFR (T790M)-cMET dual inhibitors: putative therapeutic agents for non-small-cell lung cancer

AIMnDifferent resistance mechanisms, especially, T790M secondary acquired point mutation and in some cases amplification of cMET, have been a major setback for the lung cancer therapies.nnnMETHODOLOGYnThe current in silico study explored the small molecules which can act as putative EGFR (T790M)-cMET dual inhibitors. Databases were first filtered and subsequently cross filtered, initially by thoroughly validated pharmacophore models for both targets. As per score and interactions obtained in docking, the molecules were subjected to molecular dynamics simulations, to study the stability and binding orientations of their complexes with target proteins.nnnCONCLUSIONnMolecular dynamics simulations predicted three hits to possess good binding affinities and stability for EGFR (T790M) and cMET, which can be claimed to be potential dual inhibitors.

Chemotherapeutics-resistance “arms” race: An update on mechanisms involved in resistance limiting EGFR inhibitors in lung cancer

ABSTRACT Clinical reports suggest that EGFR‐mutated lung cancer usually respond significantly towards small molecule tyrosine kinase inhibitors. Same studies also report the eventual development of acquired resistance within a median time interval of 9 to 14 months. One of the major mechanisms involved in this acquired resistance was found to be a secondary point mutation at gate‐keeper residue, EGFR T790M. However, there are other recent studies which disclose the role of few other novel key players such as, ZEB1, TOPK etc., in the development of tolerance towards the EGFR TKIs, along with other commonly known mechanisms, such as amplification of signalling pathways such as, c‐MET, Erbb2, AXL, additional acquired secondary mutations (PIK3CA, BRAF), or phenotypic transformation (small cell or epithelial to mesenchymal transitions). Interestingly, a recent study showed development of resistance via another point mutation, C797S, in case of tumors which were previously resistant and were administered agents capable of overcoming T790M gatekeeper mutation based resistance. Thus, raising serious concern over the direction of drug development involving tyrosine kinases such as EGFR. Current approaches focussing on development of third generation inhibitors, dual inhibitors or inhibitors of HSP90 have shown significant activity but do not answer the long term question of resistance.

Kinases inhibitors in lung cancer: From benchside to bedside

Lung cancer still remains one of the major causes of cancer related mortality around the globe. Various different molecular targets have been discovered till date for targeting lung cancer. But not every new molecular target has a successfully designed inhibitor; moreover conventional chemotherapeutics have their own limitations such as toxicity and lack of selectivity. Thus, kinases still remain the most effective molecular target in lung cancer therapy. Also, once-shunned kinase inhibitors have recently acquired renewed interest after the development and approval of irreversible kinase inhibitors (such as afatinib) that form covalent bonds with cysteine (or other nucleophilic residues) in the ATP-binding pocket of the kinases. Irreversible kinase inhibitors have a number of potential advantages over conventional reversible kinase inhibitors including prolonged pharmacodynamics, suitability for rational design, high potency etc. This review reveals the current knowledge of all the chemical scaffolds, approved and/or investigational, utilized as inhibitors in lung cancer. It also explains the rationale of designing these along with possible interactions with their targets, biological data and possible problems associated with these inhibitors.

Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-MET

Secondary acquired mutation in EGFR, i.e. EGFR T790M and amplification of c-MET form the two key components of resistant NSCLC. Thus, previously published pharmacophore models of EGFR T790M and c-MET were utilized to screen an in-house database. On the basis of fitness score, indole-pyrimidine scaffold was selected for further evaluation. Derivatives of indole-pyrimidine scaffold with variedly substituted aryl substitutions were sketched and then docked in both the targets. These docked complexes were then subjected to molecular dynamic simulations, to study the stability of the complexes and evaluate orientations of the designed molecules in the catalytic domain of the selected kinases. Afterwards, the complexes were subjected to MM-GBSA calculation, to study the effect of substitutions on binding affinity of double mutant EGFR towards these small molecules. Finally, the designed molecules were synthesized and evaluated for their inhibitory potential against both the kinases using in vitro experiments. Additionally, the compounds were also evaluated against EGFR (L858R) to determine their selectivity towards double mutant, resistant kinase [EGFR (T790M)]. Compound 7a and 7c were found to be possess nanomolar range inhibitory (IC50) potential against EGFR (T790M), 7u202fh showed good inhibitory potential against c-MET with IC50 value of 0.101u202fµM. Overall, this work is one of the earliest report of compounds having significant dual inhibitory potential against secondary acquired EGFR and cMET, with IC50 values in nanomolar range.

Success stories of natural product-based hybrid molecules for multi-factorial diseases

Complex diseases comprises of highly complicated etiology resulting in limited applicability of conventional targeted therapies. Consequently, conventional medicinal compounds suffer major failure when used for such disease conditions. Additionally, development of multidrug resistance (MDR), adverse drug reactions and clinical specificity of single targeted drug therapy has increased thrust for novel drug therapy. In this rapidly evolving era, natural product-based discovery of hybrid molecules or multi-targeted drug therapies have shown promising results and are trending now a days. Historically, nature has blessed human with different sources viz. plant, animal, microbial, marine and ethnopharmaceutical sources which has given a wide variety of medicinally active compounds. These compounds from natural origin are always choice of interest of medicinal chemists because of their minimum side effects. Hybrid molecules synthesized by fusing or conjugating different active molecules obtained from these sources are reported to synergistically block different pathways which contribute in the pathogenesis of complex diseases. This review strives to encompass all natural product-derived hybrid molecules which act as multi-targeting agents striking various targets involved in different pathways of complex diseased conditions reported in literature.

In-silico guided development of imine based inhibitors for resistance-deriving kinases

Abstract Two major mechanisms involved in resistant NSCLC (non-small cell lung cancer) include secondary acquired mutation in EGFR (epidermal growth factor receptor), that is, EGFR T790M and amplification of c-MET (hepatocyte growth factor receptor). Thus, already established pharmacophore models of EGFR T790M and c-MET were employed to filter-out an in-house database. Further fitness score led to the selection of imino-pyrimidine scaffold. Followed by sketching of imino-pyrimidine derivatives having varied aryl substitutions, which were then docked and subjected to molecular dynamic simulations, to study the orientations and conformations of the designed molecules in the catalytic domain. Molecules with hydrophobic interaction with mutant residue M790 were selected. Finally, MM-GBSA (Molecular Mechanics‐Generalized Born Surface Area) calculations were performed, to study the effect of substitutions on the binding affinity of the double mutant EGFR towards these small molecules. Finally, the designed compounds were synthesized and evaluated for their kinase inhibitory potential using in-vitro experiments. Two compounds were found to possess sub-micromolar range inhibitory potential against EGFR (T790M), while one of the compound showed significant selective inhibitory potential against c-MET. Additionally, one compound was found to possess significant dual inhibitory potential against these target kinases. Communicated by Ramaswamy H. Sarma

The Current Status of O-Heterocycles: A Synthetic and Medicinal Overview

O‐Heterocycles have been explored in the field of medicinal chemistry for a long time, but their significance has not been duly recognised and they are often shunned in favour of N‐heterocycles. The design of bioactive molecules for nearly every pathophysiological condition is primarily focused on novel N‐heterocycles. The main reasons for such bias include the ease of synthesis and possible mimicking of physiological molecules by N‐heterocycles. But considering only this criterion rarely provides breakthrough molecules for a given disease condition, and instead the risks of toxicity or side effects are increased with such molecules. On the other hand, owing to improved synthetic feasibility, O‐heterocycles have established themselves as equally potent lead molecules for a wide range of pathophysiological conditions. In the last decade there have been hundreds of reports validating the fact that equally potent molecules can be designed and developed by using O‐heterocycles, and these are also expected to have comparably low toxicity. Even so, researchers tend to remain biased toward the use of N‐heterocycles over O‐heterocycles. Thus, this review provides a critical analysis of the synthesis and medicinal attributes of O‐heterocycles, such as pyrones, oxazolones, furanones, oxetanes, oxazolidinones, and dioxolonones, and others, reported in the last five years, underlining the need for and the advantages guiding researchers toward them.

Chemical classes targeting energy supplying GyrB domain of Mycobacterium tuberculosis

Tuberculosis (TB) is contagious in nature and immunocompromised patients have a higher probability of developing TB. The occurrence of drug resistance, has led to serious health concerns in the management of TB. In order to combat resistant tuberculosis there is an urgent need of identifying new drug targets and new drug combinations for the effective management and reduction in the duration of TB treatment. Targeting DNA gyrase that is involved in bacterial replication cycle, provides one rationale approach. Various fluoroquinolone based drugs have shown promising effect against DNA gyrase enzyme and in turn were successful in combat against MDR TB. However, GyrA domain mutations based resistance towards fluoroquinolones has put a question mark over current therapies for tuberculosis. Fluoroquinolones target GyrA domain of bacterial DNA gyrase therefore targeting DNA GyrB domain may overcome this resistance issue, establishing it as an attractive target. This review is a compilation of current research efforts on energy supplying domain of Mycobacterium tuberculosis that could provide breakthrough in development of more potent Mtb DNA GyrB inhibitors.

In silico designing of domain B selective gyrase inhibitors for effective treatment of resistant tuberculosis

One of the major mechanisms followed by the therapeutic agents to target the causative organism of TB, Mycobacterium tuberculosis, involves disruption of its DNA replication cycle. The process of replication involves two steps, i.e., breakage and reunion of DNA at gyrase A (GyrA) domain and ATP hydrolysis at gyrase B (GyrB) domain, both occur simultaneously. Current therapy for multi-drug resistant TB (MDR-TB) involves FDA approved, fluoroquinolone-based antibiotics, which act by targeting replication process at GyrA domain. However, resistance against fluoroquinolones due to mutations in the GyrA domain has limited the use of this therapy and shifted the focus of research community on GyrB domain. Thus, in the present study novel chemotherapeutic agents for resistant TB were designed by exploring GyrB domain using in silico techniques. Pharmacophore model of GyrB domain was employed for screening an In-house database. Followed by cross-screening via a qualitative Hip-Hop pharmacophore model for GyrA to remove non-selective gyrase B inhibitors. Further molecular dynamics simulations and MM-GBSA calculations were performed to determine stability and binding affinity of the screened molecules. These analyses resulted in five putative oxindole based selective GyrB domain inhibitors, which were synthesized and evaluated for anti-tubercular activity against M. tuberculosis H37Rv strain. Two compounds exhibited significant anti-TB activity, whereas other three compounds were found to be outliers of the in silico study.

Benzimidazole: Journey From Single Targeting to Multitargeting Molecule

Abstract There have been continuous efforts to discover multitargeting agents to counter several complex, multifactorial pathological conditions. Of various heterocycles explored for multitargeting potential, benzimidazole has significant potential as suggested in literature. Benzimidazole forms a major class of heterocycles, being in multiple categories of drugs such as anticancer, antimicrobials, antivirals, antiparasites, and more. This heterocycle nucleus provides a useful scaffold for the design and development of new therapeutic agents. Literature provides evidence for a vast pharmacological profile associated with various substituted benzimidazole nuclei. Despite such noteworthy competency, the benzimidazole nucleus is largely considered a more exhausted and pharmacologically saturated heterocycle. This chapter covers various aspects of benzimidazole including chemistry, pharmacological prospects, and its role as a multitargeting agent in multifactorial diseases. This chapter will aid both members of medicinal chemistry and nonmedicinal chemistry communities to understand the role of the benzimidazole nucleus in development of several key therapeutic agents for multifactorial diseases.