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.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy.

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.

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Covalent Inhibition in Drug Discovery.

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.

Advances in covalent kinase inhibitors.

Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors.

Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance.

Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC).

Design and synthesis of quinazolinones as EGFR inhibitors to overcome EGFR resistance obstacle

Cardiotoxicity is one amongst the adverse effect of Osimertinib delineate in clinical trials and related to escalating doses. To triumph over the drawbacks of Osimertinib, in this study, we tend to...

Design and synthesis of novel 2,4-disubstituted aminopyrimidines: reversible non-covalent T790M EGFR inhibitors.

Selective inhibitors of CYP isoforms gaining importance in the treatment of cancers caused by hormonal imbalance. Metabolites of estradiol and polyaromatic hydrocarbons generated due to CYP1B1 activity were reported to be oncogenic. The selective CYP1B1 inhibitors could have the potential therapeutic utility in controlling the cancer due to these oncogens. Due to the CYP isoforms high sequence similarity the design of selective CYP inhibitor is difficult. Recently our group has reported two novel chemical classes (scaffolds) that are specific towards CYP1B1. The chemical architecture of these compounds should give valuable information for its selectivity and potency against CYP1B1. Overlay of our compounds and ANF by Shape and electrostatic based similarity and molecular docking displayed different orientations. Moreover the study has shown the overlay of three atom bridge of selective inhibitor superimposed on –O-CHlinking aryl groups rather than –CO-CH=CHof ANF. Molecular docking simulation revealed that the selective inhibitors are either establishing H-bonding interaction with Asp333 or π-π staking interaction Phe231 and Phe268. Molecular docking simulation has provided much more information rather than simple shape and electrostatic based similarity study. Crucial H-bonding interactions and π-π staking interactions responsible for selectivity towards CYP1B1 were identified. Two atom linker between the aryl groups matter, cyclization simply ensures the planarity of ANF and quinazolines.

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Azim Ansari

Papers

Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance.

Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC).

Design and synthesis of quinazolinones as EGFR inhibitors to overcome EGFR resistance obstacle

Design and synthesis of novel 2,4-disubstituted aminopyrimidines: reversible non-covalent T790M EGFR inhibitors.

Comparative Computational Studies on Selective CytochromeP450 1B1 Inhibitors