CO-1686

• CAT Number: I001446
• CAS Number: 1374640-70-6
• Molecular Formula: C27H28F3N7O3
• Molecular Weight: 555.6
• Purity: ≥95%
• Synonyms: N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
• Target: EGFR
• Solubility: DMSO: ≥ 43 mg/mL
• Storage: Store at -20°C
• IC50: 21.5±1.7 nM (EGFRL858R/T790M); 303.3 ± 26.7 nM (EGFRWT)
• InChI: InChI=1S/C27H28F3N7O3/c1-4-24(39)32-18-6-5-7-19(14-18)33-25-21(27(28,29)30)16-31-26(35-25)34-22-9-8-20(15-23(22)40-3)37-12-10-36(11-13-37)17(2)38/h4-9,14-16H,1,10-13H2,2-3H3,(H,32,39)(H2,31,33,34,35)
• InChIKey: HUFOZJXAKZVRNJ-UHFFFAOYSA-N
• SMILES: O=C(C=C)NC1=CC=CC(NC2=NC(NC3=CC=C(N4CCN(C(C)=O)CC4)C=C3OC)=NC=C2C(F)(F)F)=C1

CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M(IC50=21 nM).
IC50 Value: 21.5±1.7 nM (EGFRL858R/T790M); 303.3 ± 26.7 nM (EGFRWT) [1]
in vitro: CO-1686 is a potent inhibitor of EGFR L858R/T790M kinase (kinact/Ki = (2.41 ± 0.30) x 105 M-1s-1) and is approximately 22-fold selective over WT EGFR (kinactt/Ki = (1.12 ± 0.14) x 104 M-1s-1). CO-1686 potently inhibited proliferation in the mutant-EGFR NSCLC cellswith GI50 values ranging from 7 – 32 nM. In comparison, the GI50 value for A431 cells, an epidermoid cell line that is driven by amplified WT EGFR(19), was 547 nM. Two cell lines
expressing WT EGFR in the presence of an N- or KRAS mutation (NCI-H1299 and NCI-H358,
respectively) were inhibited by CO-1686 at a concentration of 4275 and 1806 nM, respectively [1].
in vivo: CO-1686 displayed high oral bioavailability (65%) and a relatively long half-life of 2.6 hours when dosed at 20 mg/kg. Tumor-bearing mice were dosed orally once daily with CO-1686 as single agent and its effect on tumor growth was determined in several EGFR dependent xenograft models (Fig. 3A-C). Continuous oral dosing of CO-1686 causes dose-dependent and significant tumor growth inhibition in all EGFR-mutant models examined. At 100 mg/kg/day CO-1686 caused tumor regressions in two erlotinib-resistant models expressing the L858R/T790M EGFR mutation, the NCI-H1975 cell line xenograft and the patient-derived lung tumor xenograft (PDX) LUM1868, while erlotinib had no inhibitory effect on tumor growth [1].
Toxicity:N/A
Clinical trial: Study to Evaluate Safety, Pharmacokinetics, and Preliminary Efficacy of CO-1686 in Previously Treated Mutant Epidermal Growth Factor Receptor (EGFR) N… Phase1/2

Reference

1:Clin Cancer Res. 2016 May 15;22(10):2386-95. doi: 10.1158/1078-0432.CCR-15-1260. Epub 2016 Jan 8. Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686).Karlovich C,Goldman JW,Sun JM,Mann E,Sequist LV,Konopa K,Wen W,Angenendt P,Horn L,Spigel D,Soria JC,Solomon B,Camidge DR,Gadgeel S,Paweletz C,Wu L,Chien S,O/’Donnell P,Matheny S,Despain D,Rolfe L,Raponi M,Allen AR,Park K,Wakelee H, PMID: 26747242 DOI: 10.1158/1078-0432.CCR-15-1260 Abstract: PURPOSE: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors.EXPERIMENTAL DESIGN: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing.RESULTS: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 – 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 – 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response.CONCLUSIONS: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. ©2016 AACR.©2016 American Association for Cancer Research.