Description: Brigatinib, also known as AP-26113, is an orally active, potent and selective Dual ALK/EGFR inhibitor. AP26113 binds to and inhibits ALK kinase and ALK fusion proteins as well as EGFR and mutant forms. This leads to the inhibition of ALK kinase and EGFR kinase, disrupts their signaling pathways and eventually inhibits tumor cell growth in susceptible tumor cells. In addition, AP26113 appears to overcome mutation-based resistance. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development; ALK dysregulation and gene rearrangements are associated with a series of tumors. EGFR is overexpressed in a variety of cancer cell types.
Synonym: AP26113; AP-26113; AP 26113, Brigatinib
IUPAC/Chemical Name: (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
Name: Brigatinib (AP-26113)
Chemical Formula: C29H39ClN7O2P
Exact Mass: 583.25914
Molecular Weight: 584.10176
Elemental Analysis: C, 59.63; H, 6.73; Cl, 6.07; N, 16.79; O, 5.48; P, 5.30
The following public resources have listed a wrong structure for Brigatinib (AP-26113)
1. Some papers:
Such as Onco Targets Ther. 2014 Mar 5;7:375-85., http://www.ncbi.nlm.nih.gov/pubmed/24623980.
2. Wikipedia (https://en.wikipedia.org/wiki/Brigatinib, last visited on 12/9/2015).
3. Sci-Finder Scholar Database: Before December 2015, Sci-Finder Scholar Database also wrongly listed CAS#1197958-12-5 as Brigatinib (AP26113). Now Sci-Finder Scholar Database has corrected.
4. Pubchem: https://pubchem.ncbi.nlm.nih.gov/compound/ap26113, last visited: 12/9/2015.
————————————————— More information related to AP26113 bioactivities———————————————
AP26113 is a potent and selective ALK inhibitor. AP26113 induced tumor regression in BaF3 xenograft model expressing EML4-ALK, and EML4-ALK harboring G1269S and L1196M (gatekeeper) mutations. In preclinical studies, AP26113 was shown to be active against all 9 clinically-identified crizotinib-resistant mutants tested. AP26113 is also a potent, reversible inhibitor of activated and T790M-mutant EGFR, yet it does not inhibit the native enzyme . A phase I/II study was initiated (NCT01449461) to evaluate AP26113 as a dual ALK/mutant EGFR inhibitor. As of 14 Jan 2013, 44 patients were enrolled including 37 with NSCLC. In the dose escalation phase (30-300 mg), two dose limiting toxicities were observed, grade 3 ALT elevations at 240 mg and grade 4 dyspnea at 300 mg. The recommended phase II dose was identified as 180 mg. The most common adverse effects were nausea (45%), fatigue (39%), diarrhea (27%). Among 18 evaluable ALK+ patients, four out of 5 patients with CNS lesions showed improvement on follow up imaging, including one patient resistant to crizotinib and ceritinib. Sixteen patients had EGFR mutation (EGFRm). Of 12 patients with EGFRm, one patient responded at 120 mg (duration 21 weeks, ongoing) and 6 patients had stable disease (2 ongoing, duration 7 and 31 weeks, respectively). In a later update, 114 pts were enrolled: 65 in phase 1 (30–300 mg) and 49 in phase 2 (180 mg) . There were 106 pts with NSCLC. The most common treatment-emergent AEs (20%) were similar to the previous report. Early onset of pulmonary symptoms (dyspnea with hypoxia and/or findings on imaging) were observed in 6/45 (13%) pts at 180 mg QD. These symptoms needed urgent intervention. The respiratory symptoms were not observed at 90 mg QD (n = 8) or in the lead-in dose cohort (n = 19; initiated at 90 mg QD, escalated to 180 mg QD after 1 wk). Therefore, further enrollment with this dose escalation scheme, and an additional cohort of 90 mg QD without escalation were being added. Among 38 evaluable ALK+ NSCLC pts who had prior crizotinib, 24 (63%) reported response, including one CR. Six of 10 pts enrolled with untreated or progressing brain metastases showed response in brain, including 4 with complete resolution; 2 stable disease, 2 progressed; AP26113 has promising anti-tumor activity in pts with crizotinib-resistant ALK+ NSCLC, including pts with brain metastases. A randomized phase 2 trial of AP26113 comparing 90 mg QD vs. 90 mg QD escalating to 180 mg QD in crizotinib-resistant ALK+ NSCLC was planned. (copied from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349797/)
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