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Rahul Pawara

Bio: Rahul Pawara is an academic researcher. The author has contributed to research in topics: T790M & EGFR inhibitors. The author has an hindex of 7, co-authored 21 publications receiving 164 citations.

Papers
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Journal ArticleDOI
TL;DR: This review summarizes the third generation inhibitors, synthesis, their mechanism of resistance and latest development on the discovery of a fourth-generation EGFR TKIs and U to Y allosteric strategies to combat the C797S EGFR resistance problem.

113 citations

Journal ArticleDOI
TL;DR: Results indicate that the virtual screened compounds could be potential leads for the further development of new allosteric EGFR T790M/C797S inhibitors to overcome the problem of drug resistance.
Abstract: Third generation EGFR inhibitor osimertinib was approved as the first-line treatment for EGFR T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients in 2017. However, EGFR tertiary Cys...

32 citations

Journal ArticleDOI
TL;DR: Wang et al. as mentioned in this paper designed and synthesized two series of acrylamide linked quinazolines for EGFR T790M inhibitors, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975.

32 citations

Journal ArticleDOI
TL;DR: New derivatives of 4(3H)-quinazolinones synthesized and evaluated for their inhibitory activity against NSCLC showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant.

30 citations

Journal ArticleDOI
TL;DR: This critical analysis of the structure of bedaquiline will help medicinal chemists to synthesize the better modified analouge of bedquiline with reduced cardiotoxicity, hepatotoxicity potential and improved pharmacokinetics.

27 citations


Cited by
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20 Sep 2013
TL;DR: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
Abstract: Purpose The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

2,380 citations

Journal Article
01 Jan 2005-Blood
TL;DR: In this paper, the crystal structure of the Jak3 kinase domain in complex with staurosporine analog AFN941 is presented, with both activation loop tyrosine residues phosphorylated, suggesting a direct mechanism by which the C-helix is induced by phosphorylation of the activation loop.

155 citations

Journal ArticleDOI
TL;DR: The recent advances on the discovery and development of different EGFR inhibitors and the use of various therapeutic strategies such as multi-targeting agents and combination therapies have also been reviewed.

153 citations

Journal ArticleDOI
TL;DR: This review surveys enzymes that can be targeted by covalent inhibitors for the treatment of human diseases, focusing on protein kinases, RAS proteins, and a few other enzymes that have been studied extensively as targets for covalents.
Abstract: Although covalent inhibitors have been used as therapeutics for more than a century, there has been general resistance in the pharmaceutical industry against their further development due to safety concerns. This inclination has recently been reverted after the development of a wide variety of covalent inhibitors to address human health conditions along with the US Food and Drug Administration (FDA) approval of several covalent therapeutics for use in humans. Along with this exciting resurrection of an old drug discovery concept, this review surveys enzymes that can be targeted by covalent inhibitors for the treatment of human diseases. We focus on protein kinases, RAS proteins, and a few other enzymes that have been studied extensively as targets for covalent inhibition, with the aim to address challenges in designing effective covalent drugs and to provide suggestions in the area that have yet to be explored.

147 citations

Journal ArticleDOI
TL;DR: A comprehensive overview of covalent kinase inhibitors reported in the literature over a decade period, 2007-2018 is provided, with emphasis on the rationale behind warhead choice, optimization approach, and inhibitor design.
Abstract: Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords a unique set of advantages as well as challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, covalent inhibitors irreversibly modify a proximal nucleophilic residue on the protein via reaction with an electrophile. To date, the acrylamide group remains the predominantly employed electrophile in CKI development, with its incorporation in the majority of clinical candidates and FDA approved covalent therapies. Nonetheless, in recent years considerable efforts have ensued to characterize alternative electrophiles that exhibit irreversible or reversibly covalent binding mechanisms towards cysteine thiols and other amino acids. This review article provides a comprehensive overview of CKIs reported in the literature over a decade period, 2007-2018. Emphasis is placed on the rationale behind warhead choice, optimization approach, and inhibitor design. Current FDA approved CKIs are also highlighted, in addition to a detailed analysis of the common trends and themes observed within the listed data set.

122 citations