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1374640-70-6 (CO-1686)

1

Identification

CO-1686 CO-1686
Name CO-1686
Formula C27H28F3N7O3
MW 555.55
CAS No. 1374640-70-6
EINECS
Smiles C=CC(NC1=CC=CC(NC2=NC(NC3=CC=C(N4CCN(C(C)=O)CC4)C=C3OC)=NC=C2C(F)(F)F)=C1)=O
Synonyms AVL-301;CNX-419; N-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide
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)
2

Introduction

CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M(IC50=21 nM).

Background Information

An orally bioavailable irreversible EGFR inhibitor ......by AOBIOUS INC
Rociletinib, also known as CO-1686, is an irreversible tyrosine kinase inhibitor with a Ki of 21.5 nM for the EGFR L858R/T790M mutant and a Ki of 303.3 nM for wt EGFR. It inhibited the growth of non-small cell lung cancer (NSCLC) cells expressing mutant EGFR, and it induced apoptosis. It also demonstrated in vivo anti-tumor activity in mice bearing NSCLC tumors with activating EGFR mutations. Walter A.O., et al. "Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC." Cancer Discov. 3: 1404-1415 (2013). The T790M mutation is the most common reason for acquired resistance to existing EGFR inhibitors in NSCLC. Rociletinib potently inhibited mutant EGFR L858R/T790M with an IC50 < 0.51nM. Rociletinib blocked the growth of T790M-positive NSCLC cells in vitro and in vivo. Walter A.O., et al. "CO-1686, a novel mutant-selective EGFR inhibitor, overcomes T790M mediated resistance in non-small cell lung cancer (NSCLC)." http://www.clovisoncology.com/assets/pdf/CO-1686/Clovis-Avila_AACR_2012_CO-1686_Poster_ClovisFINAL_27MAR12.pdf A phase I clinical trial in patients with EGFR mutated NSCLC demonstrated that rociletinib was well tolerated, and activity was observed in dose escalation cohorts. Sequist L.V., et al. "First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M." http://www.clovisoncology.com/files/CLVS_ASCO_2013_poster_CO1686_P1monotx_abstract2524.pdf ......by LC Laboratoies
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 ......by MedChemexpress Co., Ltd.
CO-1686, also know as AVL-301, is an orally available small molecule, irreversible inhibitor of epidermal growth factor receptor (EGFR) with potential antineoplastic activity. EGFR inhibitor CO-1686 binds to and inhibits mutant forms of EGFR, including T790M, thereby leading to cell death of resistant tumor cells. Compared to other EGFR inhibitors, CO-1686 inhibits T790M, a secondary acquired resistance mutation, as well as other mutant EGFRs and may have therapeutic benefits in tumors with T790M-mediated resistance to other EGFR tyrosine kinase inhibitors. This agent shows minimal activity against wild-type EGFR, hence does not cause certain dose-limiting toxicities. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus). Shelf life: >2 years if stored properly Drug formulation: This drug may be formulated in DMSO ......by MedKoo Biosciences, Inc.
Rociletinib (CO-1686, AVL-301) is an irreversible, mutant-selective EGFR inhibitor with Ki of 21.5 nM and 303.3 nM for EGFRL858R/T790M and EGFRWT in cell-free assays, respectively. Phase 2. ......by Selleck Chemicals LLC
CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M(IC50=21 nM). ......by Target Molecule Corp.
3

Protocol(Only for Reference)

Cell Experiment

Cell lines NSCLC cell lines expressing mutant EGFR (HCC827, PC9, HCC827-EPR, and NCI-H1975) and cell lines expressing WT EGFR (A431, NCI-H1299, and NCI-H358)
Conditions ~10 μM; 72 hours
Method Cells are seeded at 3,000 cells per well in growth media supplemented with 5% FBS, 2 mmol/L, L-glutamine, and 1% penicillin–streptomycin, allowed to adhere overnight, and treated with a dilution series of test compounds for 72 hours. Cell viability is determined by CellTiter-Glo, and results are represented as background-subtracted relative light units normalized to a dimethyl sulfoxide (DMSO)–treated control. Growth inhibition (GI 50) values are determined by GraphPad Prism 5.04. MK-2206 and XL-880 compounds are obtained from Selleck Chemical. CI data are generated using CalcuSyn.
Source Selleck Chemicals LLC

Animal Experiment

Animal Models Human EGFRL858R- and EGFRL858R/T790M-expressing transgenic mice.
Dosage ~50 mg/kg
Formulation DMSO: Solutol HS15: PBS (5:15:80; v:v:v)
Administration Oral gavage
Source Selleck Chemicals LLC
4

Physical and Chemical Properties

Appearance:White to off-white Solid EBNumber:EB000014043

Storage condition

Storage condition:Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). Stock solution storage:0 - 4 C for short term (days to weeks), or -20 C for long term (months). Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs. by MedKoo Biosciences, Inc.

Solubility

DMSO by MedChemexpress Co., Ltd.
Soluble in DMSO, not in water by MedKoo Biosciences, Inc.
(25°C) * In vitro DMSO 100 mg/mL (180.0 mM); Water<1 mg/mL (<1 mM); Ethanol<1 mg/mL (<1 mM); In vivo 1% DMSO+30% polyethylene glycol+1% Tween 8030 mg/mL by Selleck Chemicals LLC
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Mechanism and Indication

Signaling Pathways JAK/STAT Signaling Protein Tyrosine Kinase/RTK
Target EGFR
Research Area Cancer
Indications Non-small-cell lung cancer
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Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase
CO-1686 Clovis Oncology Inc Non-small-cell lung cancer 2012/3/31 2015/9/30 Phase 2 Clinical
CO-1686 - Phase 3
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Safety Data of CO-1686

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Spectral Information

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Suppliers List

Company Price and Availability Country/Region
AOBIOUS INC 1mg/USD15() USA
CHEMSCENE, LLC USA
LC Laboratoies 10mg/USD82(In stock);25mg/USD119(In stock);50mg/USD169(In stock);100mg/USD259(In stock);200mg/USD435(In stock);500mg/USD815(In stock) USA
MedChemexpress Co., Ltd. 5mg/USD50(In stock);10mg/USD80(In stock);50mg/USD165(In stock);100mg/USD255(In stock);200mg/USD400(In stock);500mg/USD550(In stock) USA
MedKoo Biosciences, Inc. USA
Pure Chemistry Scientific Inc. 10mg/USD98(In stock) USA
Selleck Chemicals LLC 10mg/USD297(In stock);50mg/USD970(In stock) USA
Shanghai Haoyuan Chemexpress Co., Ltd. 5mg/USD120(In stock);10mg/USD150(In stock);50mg/USD400(In stock);100mg/USD550(In stock) China
Target Molecule Corp. 10mg/USD77();50mg/USD156();100mg/USD247() USA
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Related Products

Other Forms of 1374640-70-6

Name CAS No Formula MW
CO-1686 (hydrobromide) 1446700-26-0 C27H29BrF3N7O3 636.46

Recommended Compounds in EGFR

Name CAS No Formula MW
Ginsenoside Rh2 78214-33-2 C36H62O8 622.87
Mutated EGFR-IN-1 1421372-66-8 C25H31N7O 445.56
AZD-9291 (mesylate) 1421373-66-1 C29H37N7O5S 595.71
Mutant EGFR inhibitor 1421373-62-7 C27H30ClN7O2 520.03
AZD-9291 1421373-65-0 C28H33N7O2 499.61
WHI-P180 (hydrochloride) 153437-55-9 C16H16ClN3O3 333.77
WHI-P180 211555-08-7 C16H15N3O3 297.31
Gefitinib (hydrochloride) 184475-55-6 C22H25Cl2FN4O3 483.36
Erlotinib (mesylate) 248594-19-6 C23H27N3O7S 489.54
BGB-102 807640-87-5 C22H25BrN4O2 457.36
Poziotinib 1092364-38-9 C23H21Cl2FN4O3 491.34
CO-1686 (hydrobromide) 1446700-26-0 C27H29BrF3N7O3 636.46
CNX-2006 1375465-09-0 C26H27F4N7O2 545.53
PD 168393 194423-15-9 C17H13BrN4O 369.22
AG 18 118409-57-7 C10H6N2O2 186.17
Afatinib (dimaleate) 850140-73-7 C32H33ClFN5O11 718.08
Chrysophanic acid 481-74-3 C15H10O4 254.24
AG-1478 153436-53-4 C16H14ClN3O2 315.75
Mubritinib 366017-09-6 C25H23F3N4O2 468.47
AST-1306 (TsOH) 1050500-29-2 C31H26ClFN4O5S 621.08

Recommended Compounds in Same Indication

Name CAS No Formula MW
Crizotinib 877399-52-5 C21H22Cl2FN5O 450.34
AT-101 90141-22-3 C30H30O8 518.55
Dovitinib 405169-16-6 C21H21FN6O 392.43
Retaspimycin 857402-23-4 C31H45N3O8 587.7
Retaspimycin (Hydrochloride) 857402-63-2 C31H46ClN3O8 624.17
Motesanib (Diphosphate) 857876-30-3 C22H29N5O9P2 569.44
Anamorelin (hydrochloride) 861998-00-7 C31H43ClN6O3 583.16
LY2603618 911222-45-2 C18H22BrN5O3 436.3
AT13387 912999-49-6 C24H31N3O3 409.52
Carboplatin 41575-94-4 C6H12N2O4Pt 371.25
Vandetanib (hydrochloride) 524722-52-9 C22H25BrClFN4O2 511.81
Dinaciclib 779353-01-4 C21H28N6O2 396.49
XL-647 781613-23-8 C24H25Cl2FN4O2 491.39
YM-155 781661-94-7 C20H19BrN4O3 443.29
Crenolanib 670220-88-9 C26H29N5O2 443.54
Ezatiostat 168682-53-9 C27H35N3O6S 529.65
Roscovitine 186692-46-6 C19H26N6O 354.45
Vandetanib (trifluoroacetate) 338992-53-3 C24H25BrF4N4O4 589.38
Anamorelin (Fumarate) 339539-92-3 C35H46N6O7 662.78
Vinorelbine 71486-22-1 C45H54N4O8 778.93
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Route of Synthesis

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References

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More Information

CO-1686

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