Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Saudi Pharm J
2018 Sep 01;266:755-763. doi: 10.1016/j.jsps.2018.04.010.
Show Gene links
Show Anatomy links
A comprehensive review on Brigatinib - A wonder drug for targeted cancer therapy in non-small cell lung cancer.
Bedi S
,
Khan SA
,
AbuKhader MM
,
Alam P
,
Siddiqui NA
,
Husain A
.
???displayArticle.abstract???
The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using N-[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90 mg of brigatinib for 7 days and then 180 mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need.
Camidge,
Acquired resistance to TKIs in solid tumours: learning from lung cancer.
2014, Pubmed
Camidge,
Acquired resistance to TKIs in solid tumours: learning from lung cancer.
2014,
Pubmed
Chan,
Targeted therapy for non-small cell lung cancer: current standards and the promise of the future.
2015,
Pubmed
Chiarle,
The anaplastic lymphoma kinase in the pathogenesis of cancer.
2008,
Pubmed
Costa,
CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib.
2011,
Pubmed
Cross,
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
2014,
Pubmed
Dalgarno,
Structural basis of Src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-based compounds.
2006,
Pubmed
Ercan,
EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors.
2015,
Pubmed
Friboulet,
The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.
2014,
Pubmed
Gao,
Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials.
2012,
Pubmed
Gettinger,
Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial.
2016,
Pubmed
Giaccone,
Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer.
2005,
Pubmed
Hatcher,
Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation.
2015,
Pubmed
Huang,
Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.
2014,
Pubmed
Huang,
Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase.
2016,
Pubmed
Iams,
Anaplastic Lymphoma Kinase as a Therapeutic Target in Non-Small Cell Lung Cancer.
2015,
Pubmed
Inoue,
Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).
2013,
Pubmed
Jang,
Discovery of a potent dual ALK and EGFR T790M inhibitor.
2017,
Pubmed
Kadi,
LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways.
2018,
Pubmed
Katayama,
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012,
Pubmed
Kim,
Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial.
2017,
Pubmed
Kobayashi,
EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.
2005,
Pubmed
Kohno,
RET fusion gene: translation to personalized lung cancer therapy.
2013,
Pubmed
Kosaka,
Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib.
2006,
Pubmed
Laurence,
The pK(BHX) database: toward a better understanding of hydrogen-bond basicity for medicinal chemists.
2009,
Pubmed
Maemondo,
Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
2010,
Pubmed
Markham,
Brigatinib: First Global Approval.
2017,
Pubmed
Marsilje,
Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.
2013,
Pubmed
Melosky,
Review of EGFR TKIs in Metastatic NSCLC, Including Ongoing Trials.
2014,
Pubmed
Mitsudomi,
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
2010,
Pubmed
Mologni,
Inhibitors of the anaplastic lymphoma kinase.
2012,
Pubmed
O'Hare,
Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML.
2004,
Pubmed
Patel,
Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance.
2017,
Pubmed
Rivera,
Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens.
2011,
Pubmed
Rosell,
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
2012,
Pubmed
Sabari,
The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers.
2017,
Pubmed
Sher,
Small cell lung cancer.
2008,
Pubmed
Smith,
Beyond C, H, O, and N! Analysis of the elemental composition of U.S. FDA approved drug architectures.
2014,
Pubmed
Solomon,
First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
2014,
Pubmed
Tanimoto,
Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells.
2014,
Pubmed
,
Echinobase
Thress,
Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M.
2015,
Pubmed
Uchibori,
Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer.
2017,
Pubmed
Walter,
Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.
2013,
Pubmed
Webb,
Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy.
2009,
Pubmed
West,
A novel classification of lung cancer into molecular subtypes.
2012,
Pubmed
Wong,
The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS.
2009,
Pubmed
,
Echinobase
Wu,
Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens.
2017,
Pubmed
Yang,
Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.
2015,
Pubmed
Yu,
Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.
2013,
Pubmed
Zappa,
Non-small cell lung cancer: current treatment and future advances.
2016,
Pubmed
Zhang,
The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models.
2016,
Pubmed
Zhou,
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.
2011,
Pubmed
Zhou,
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.
2009,
Pubmed
