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The Journal of Physical Chemistry. B Nov 2023Covalent drug discovery has been a challenging research area given the struggle of finding a sweet balance between selectivity and reactivity for these drugs, the lack... (Review)
Review
Covalent drug discovery has been a challenging research area given the struggle of finding a sweet balance between selectivity and reactivity for these drugs, the lack of which often leads to off-target activities and hence undesirable side effects. However, there has been a resurgence in covalent drug design following the success of several covalent drugs such as boceprevir (2011), ibrutinib (2013), neratinib (2017), dacomitinib (2018), zanubrutinib (2019), and many others. Design of covalent drugs includes many crucial factors, where "evaluation of the binding affinity" and "a detailed mechanistic understanding on covalent inhibition" are at the top of the list. Well-defined experimental techniques are available to elucidate these factors; however, often they are expensive and/or time-consuming and hence not suitable for high throughput screens. Recent developments in methods provide promise in this direction. In this report, we review a set of recent publications that focused on developing and/or implementing novel techniques in "Computational Covalent Drug Discovery (CCDD)". We also discuss the advantages and disadvantages of these approaches along with what improvements are required to make it a great tool in medicinal chemistry in the near future.
Topics: Drug Discovery; Drug Design
PubMed: 37921534
DOI: 10.1021/acs.jpcb.3c04710 -
Zhonghua Yi Xue Za Zhi Oct 2023The incidence and mortality of lung cancer rank first among malignant tumors in China. Among them, non-small cell lung cancer (NSCLC) is the most important pathological...
The incidence and mortality of lung cancer rank first among malignant tumors in China. Among them, non-small cell lung cancer (NSCLC) is the most important pathological type, accounting for 80%-85% of lung cancer patients, including adenocarcinoma, squamous cell carcinoma and other pathological subtypes. In recent years, with the discovery of epidermal growth factor receptor (EGFR) gene and the successful development of tyrosine kinase inhibitors (TKIs), the treatment efficacy of stage Ⅳ NSCLC patients with EGFR gene sensitive mutation has been greatly improved. As of August 23, 2023, the first generation EGFR-TKIs, gefitinib, icotinib, and erlotinib; the second generation EGFR-TKIs, afatinib and dacomitinib; and the third generation EGFR-TKIs, osimertinib, almonertinib, furmonertinib and befotertinib were all approved for marketing by China National Medical Products Administration (NMPA). In addition, multiple domestic third-generation EGFR-TKIs are undergoing clinical trials, such as rezivertinib (BPI-7711), limertinib (ASK120067), and oritinib (SH-1028). Meanwhile, mobocertinib and sunvozertinib, which targets EGFR 20ins mutations, were also approved by NMPA. With the increasing variety of EGFR-TKIs approved for marketing subsequently, it brings confusion to clinicians when choosing specific medications, and there is an urgent need to develop relevant treatment guidelines. Hence, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists convened experts to integrate the research results of various EGFR-TKIs, and proposed the "China clinical practice guideline for epidermal growth factor receptor tyrosine kinase inhibitors in stage Ⅳ non-small cell lung cancer (version 2023)", to provide reference for better clinical practice.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Tyrosine Kinase Inhibitors; ErbB Receptors; Protein Kinase Inhibitors; Mutation
PubMed: 37879869
DOI: 10.3760/cma.j.cn112137-20230505-00725 -
BMC Cancer Oct 2023About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to...
BACKGROUND
About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to explore the efficacy and safety of dacomitinib, a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKIs), in treating uncommon EGFR-mutated advanced NSCLC.
METHODS
Treatment-naïve advanced NSCLC patients treated with dacomitinib at Hunan Cancer Hospital with uncommon EGFR mutations were evaluated. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety.
RESULT
Between December 2019 and December 2021, a total of 16 patients was included. Median PFS was 14.0 (95% CI 4.32-23.7) months, and median OS was not reached. ORR was 68.8% (95% CI 41.3 to 89.0%) and DCR was 93.8% (95%CI 69.8 to 99.8%), including three achieving complete remission (CR) and eight achieving partial remission (PR). Median PFS for patients with brain metastasis was 9.0 (95%CI 6.9 to 11.1) months. Intracranial ORR was 100%, including 2 CR and 4 PR. Major treatment-related adverse events (TRAEs) included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were ≥ grade 3 TRAEs.
CONCLUSIONS
Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Cohort Studies; Antineoplastic Agents; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 37840124
DOI: 10.1186/s12885-023-11465-2 -
Neuro-oncology Advances 2023Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as...
BACKGROUND
Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as epidermal growth factor receptor () amplified and ~50% also are mutant positive. In a previously reported multicenter phase II study, we have described the response of recurrent GBM (rGBM) patients to dacomitinib, an EGFR tyrosine kinase inhibitor (TKI). As a continuation of that report, we leverage the tumor cargo-encapsulating extracellular vesicles (EVs) and explore their genetic composition as carriers of tumor biomarker.
METHODS
Serum samples were longitudinally collected from EGFR-amplified rGBM patients who clinically benefitted from dacomitinib therapy (responders) and those who did not (nonresponders), as well as from a healthy cohort of individuals. The serum EV transcriptome was evaluated to map the RNA biotype distribution and distinguish GBM disease.
RESULTS
Using long RNA sequencing, we show enriched detection of over 10 000 coding RNAs from serum EVs. The EV transcriptome yielded a unique signature that facilitates differentiation of GBM patients from healthy donors. Further analysis revealed genetic enrichment that enables stratification of responders from nonresponders prior to dacomitinib treatment as well as following administration.
CONCLUSION
This study demonstrates that genetic composition analysis of serum EVs may aid in therapeutic stratification to identify patients with dacomitinib-responsive GBM.
PubMed: 37811539
DOI: 10.1093/noajnl/vdad104 -
Clinical and Translational Science Dec 2023This study aimed to evaluate the bioequivalence between test tablet dacomitinib and reference product Vizimpro® under fasting and fed conditions and assess their... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aimed to evaluate the bioequivalence between test tablet dacomitinib and reference product Vizimpro® under fasting and fed conditions and assess their pharmacokinetic (PK) and safety profiles for gaining marketing approval of the new generic drug. A single-center, randomized, open-label, single-dose, two-treatment, two-period, crossover bioequivalence study was conducted in healthy Chinese subjects. Eligible healthy subjects randomly received a single 45 mg dose of test or reference formulations with an administration sequence of test tablet (T), reference tablet (R), or (RT), under both fasting and fed conditions, and each single administration was followed by a 21-day washout period. Plasma concentrations and corresponding non-compartmental PK parameters of dacomitinib were determined. The 90% confidence intervals of the geometric mean ratio (GMR) (test/reference) for C , AUC , and AUC , respectively, were 97.75%-119.99%, 101.00%-115.09%, and 100.27%-113.90% under fasting conditions and 95.20%-104.94%, 97.24%-102.23%, and 97.27%-101.88% under fed conditions, which were within the limits of 80%-125%. Under fasting and fed conditions, the PK characteristics of the test dacomitinib tablet and reference Vizimpro® were comparable; the two formulations of dacomitinib were demonstrated to be bioequivalent and well-tolerated in healthy Chinese volunteers.
Topics: Humans; Therapeutic Equivalency; Cross-Over Studies; Healthy Volunteers; Fasting; Tablets; China
PubMed: 37786330
DOI: 10.1111/cts.13653 -
Molecular Biotechnology Sep 2023Lung adenocarcinoma (LUAD) is one of the most prevalent and leading causes of cancer deaths globally, with limited diagnostic and clinically significant therapeutic...
Lung adenocarcinoma (LUAD) is one of the most prevalent and leading causes of cancer deaths globally, with limited diagnostic and clinically significant therapeutic targets. Identifying the genes and processes involved in developing and progressing LUAD is crucial for developing effective targeted therapeutics and improving patient outcomes. Therefore, the study aimed to explore the RNA sequencing data of LUAD from The Cancer Genome Atlas (TCGA) and gene expression profile datasets involving GSE10072, GSE31210, and GSE32863 from the Gene Expression Omnibus (GEO) databases. The differential gene expression and the downstream analysis determined clinically significant biomarkers using a network-based approach. These therapeutic targets predominantly enriched the dysregulation of mitotic cell cycle regulation and revealed the co-overexpression of Aurora-A Kinase (AURKA) and Targeting Protein for Xklp2 (TPX2) with high survival risk in LUAD patients. The hydrophobic residues of the AURKA-TPX2 interaction were considered as the target site to block the autophosphorylation of AURKA during the mitotic cell cycle. The tyrosine kinase inhibitor (TKI) dacomitinib demonstrated the strong binding potential to hinder TPX2, shielding the AURKA destabilization. This in silico study lays the foundation for repurposing targeted therapeutic options to impede the Protein-Protein Interactions (PPIs) in LUAD progression and aid in future translational investigations.
PubMed: 37768502
DOI: 10.1007/s12033-023-00879-9 -
European Journal of Pharmacology Dec 2023The in vitro A549 cells, and A549 xenografts in nude mouse, were two commonly used models for anti-cancer drug discovery. However, the biological and molecular...
The in vitro A549 cells, and A549 xenografts in nude mouse, were two commonly used models for anti-cancer drug discovery. However, the biological and molecular characteristics of these two classic models, and also the dynamic transcriptome changes after dacomitinib exposure remains elusive. We performed single-cell RNA sequencing to define the transcriptome profile at single-cell resolution, and processed tumor samples for bulk RNA and protein analysis to validate the differently expressed genes. Transcriptome profiling revealed that the in vitro A549 cells are heterogeneous. The minimal subpopulation of the in vitro A549 cells, which were characterized by the signature of response to unfolded protein, became the overriding subpopulation of the xenografts. The EGFR non-activating A549 cells were resistant to dacomitinib in vitro, while A549 xenografts were comparatively sensitive as EGFR-activating HCC827 xenografts. Dacomitinib inhibited MAPK signaling pathway, and increased the immune response in the A549 xenografts. A phagocytosis checkpoint stanniocalcin-1 (STC1) was significantly inhibited in dacomitinib-treated xenografts. So here our study gives the first insight of the heterogeneity of the two classic models, and the translational potential of dacomitinib being used into a broader patient population rather than EGFR common activating mutation.
Topics: Animals; Mice; Humans; ErbB Receptors; Single-Cell Gene Expression Analysis; Protein Kinase Inhibitors; Quinazolinones; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutation
PubMed: 37708985
DOI: 10.1016/j.ejphar.2023.176046 -
Translational Cancer Research Aug 2023Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor... (Review)
Review
The treatment of patients with non-small cell lung cancer carrying uncommon mutations, mutations, or brain metastases: a systematic review of pre-clinical and clinical findings for dacomitinib.
BACKGROUND
Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor () mutations, human epidermal growth factor receptor 2 () mutations, or central nervous system (CNS) metastases.
METHODS
This study aimed to give a systematic review on its potential applications in the above settings by searching MEDLINE/PubMed, Embase, Cochrane Library, American Society of Clinical Oncology.org, European Society for Medical Oncology.org, and ClinicalTrials.gov.
RESULTS
The literature search yielded 649 publications in total. According to our findings, dacomitinib exhibited promising efficacy in patients with major uncommon mutations (including G719X, S768I, and L861Q). Both exon 20 insertional mutation (Ex20ins) and Ex20ins demonstrated significant internal heterogeneity in response to dacomitinib, among which specific subtypes (including D770delinsGY, A763_Y764insFQEA, and M774delinsWLV) were highly sensitive. Other uncommon mutations including 18del and L747P have also been shown responsive to dacomitinib. Interestingly, limited studies suggested dacomitinib application on certain first or third generation tyrosine kinase inhibitors (TKIs)' resistant secondary mutations. Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations.
CONCLUSIONS
Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon mutations and specific or mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.
PubMed: 37701115
DOI: 10.21037/tcr-23-95 -
Journal of Immunotherapy and Precision... Aug 2023Osimertinib is the treatment of choice for epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC). Because of its high price, many... (Review)
Review
INTRODUCTION
Osimertinib is the treatment of choice for epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC). Because of its high price, many low-income countries, such as Syria, cannot provide osimertinib, which makes it difficult to choose the appropriate treatment for these patients. This study aimed to review articles that assessed tyrosine kinase inhibitors (TKIs) for advanced NSCLC and developed an appropriate treatment plan for Syrian patients.
METHODS
An electronic literature search was conducted of published phase II and III studies that assessed the efficacy of EGFR-TKIs for advanced NSCLC between January 2003 and May 2022.
RESULTS
Seventeen articles were reviewed. The results were similar when erlotinib or icotinib was compared with gefitinib. Progression-free survival and overall survival for afatinib and dacomitinib were longer than for gefitinib, with small significant differences. Osimertinib was the only TKI that showed efficacy against the T790M mutation, which showed an improvement over the first- and second-generation TKIs. Osimertinib as a first-line therapy is not cost-effective compared with first- and second-generation TKIs.
CONCLUSION
Osimertinib is the preferred first-line treatment in patients with advanced mutated NSCLC. First- and second-generation TKIs are still considered good options, especially in low-income countries that cannot cover the costs of osimertinib.
PubMed: 37637235
DOI: 10.36401/JIPO-22-29 -
Translational Lung Cancer Research Jul 2023This review will provide an overview of and mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals. (Review)
Review
BACKGROUND AND OBJECTIVE
This review will provide an overview of and mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals.
METHODS
We obtained data from the literature in accordance with narrative review reporting guidelines.
KEY CONTENT AND FINDINGS
mutations are present in up to 15-20% of all NSCLCs; amongst these, 10% correspond to kinase domain insertions in exon 20. Structurally similar, () mutations occurs in 1-4% of NSCLCs, mostly consisting of insertions or point mutations. The majority of exon 20 insertions occur within the loop following the regulatory C-helix and activate the kinase domain of EGFR without generating a therapeutic window to gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Mobocertinib represents a novel class of covalent EGFR inhibitors with a modest therapeutic window to these mutants and induces anti-tumor responses in a portion of patients [at 160 mg/day: response rate of <30% with duration of response (DoR) >17 months and progression-free survival (PFS) of >7 months] albeit with mucocutaneous and gastrointestinal toxicities. The bi-specific EGFR-MET antibody amivantamab-vmjw has modest but broad preclinical activity in EGFR-driven cancers and specifically for exon 20 insertion-mutated NSCLC has response rates <40% and PFS of <8.5 months at the cost of both infusion-related plus on-target toxicities. Both drugs were approved in 2021. The clinical development of kinase inhibitors for -mutated NSCLC has been thwarted by mucocutaneous/gastrointestinal toxicities that preclude a pathway for drug approval, as the case of poziotinib. However, the activation of ERBB2 has allowed for repurposing of antibody-drug conjugates (ADCs) that target ERBB2 with cytotoxic payloads. The FDA approved fam-trastuzumab deruxtecan-nxki in 2022 for NSCLC based on response rate of >55%, DoR >9 months, PFS >8 months and manageable adverse events (including cytopenias, nausea and less commonly pneumonitis). Other therapies in clinical development include sunvozertinib and zipalertinib, among others. In addition, traditional cytotoxic chemotherapy has some activity in these tumors.
CONCLUSIONS
The approvals of mobocertinib, amivantamab, and trastuzumab deruxtecan represent the first examples of precision oncology for exon 20 insertion-mutated and -mutated NSCLCs.
PubMed: 37577308
DOI: 10.21037/tlcr-23-98