MedKoo Biosciences, Inc.
Tel:   +1-919-636-5577    Fax:   +1-919-980-4831    Email:   sales@medkoo.com
Search
Login Register
Search
MedKoo Cat#: 205796 | Name: Rociletinib
Featured New

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Rociletinib, also known as AVL-301 and CO1686, 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.

Chemical Structure

Rociletinib
Rociletinib
CAS#1374640-70-6 (free base)

Theoretical Analysis

MedKoo Cat#: 205796

Name: Rociletinib

CAS#: 1374640-70-6 (free base)

Chemical Formula: C27H28F3N7O3

Exact Mass: 555.2206

Molecular Weight: 555.55

Elemental Analysis: C, 58.37; H, 5.08; F, 10.26; N, 17.65; O, 8.64

Price and Availability

Size Price Availability Quantity
25mg USD 90.00 Ready to ship
50mg USD 150.00 Ready to ship
100mg USD 250.00 Ready to ship
200mg USD 450.00 Ready to ship
500mg USD 650.00 Ready to ship
1g USD 850.00 Ready to ship
2g USD 1,450.00 Ready to ship
5g USD 2,850.00 Ready to ship
10g USD 4,150.00 2 weeks
Show More
Bulk Inquiry
Buy Now
Add to Cart
Related CAS #
1374640-70-6 (free base) 1446700-26-0 (HBr)
Synonym
CO1686; CO-1686; CO 1686; AVL301; AVL 301; AVL-301; CNX419; CNX 419; CNX-419; Rociletinib.
IUPAC/Chemical Name
N-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide
InChi Key
HUFOZJXAKZVRNJ-UHFFFAOYSA-N
InChi Code
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)
SMILES Code
C=CC(NC1=CC=CC(NC2=NC(NC3=CC=C(N4CCN(C(C)=O)CC4)C=C3OC)=NC=C2C(F)(F)F)=C1)=O
Appearance
white to off-white solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
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.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
CNX-2006 is a Me-Too version of CO-1686, which structures are compared as below:     
Biological target:
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.
In vitro activity:
Selectivity and activity of CO-1686 against cells expressing EGFR mutations was demonstrated in a panel of cell lines (Fig. 2A and SI Table 2). The effect of CO-1686 treatment on cell growth was determined in 4 NSCLC cell lines expressing mutant EGFR (HCC827, PC9, HCC827-EPR and NCI-H1975) and in 3 cell lines expressing WT EGFR (A431, NCI-H1299 and NCI-H358). HCC827 and PC9 cell lines both harbor the EGFR delE746-A750 activating mutation in exon 19. HCC827-EPR is a resistant clone of HCC827 that acquired T790M in response to continuous exposure to erlotinib and the MET inhibitor PHA-665,752. NCI-H1975 is another T790M-positive cell line that harbors the EGFR L858R/T790M double mutation. CO-1686 potently inhibited proliferation in the mutant-EGFR NSCLC cells with 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, 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. Similar results were obtained when determining effects of CO-1686 on EGFR signaling by immunoblot analysis in the WT-driven A431 cells compared to the EGFR mutant cells. IC50 values for inhibition of EGFR phosphorylation were above 2000 nM in the three WT EGFR expressing cells, while CO-1686 inhibited p-EGFR with IC50 values ranging from 62 – 187 nM in the mutant-EGFR expressing cells (SI Table 2) confirming the mutant-selective properties of CO-1686. CO-1686 inhibits cell proliferation and EGFR phosphorylation equally in the parental HCC827 (EGFR del19) as well as the erlotinib-resistant HCC827-EPR (del19/T790M) clone. Treatment with CO-1686 induces apoptosis in both cell lines as demonstrated by an increase in cleaved PARP and BimEL protein (Fig. 2B), irrespective of the T790M status. Erlotinib on the other hand has no effect in the T790M-positive HCC827-EPR cells (Fig. 2B). Additionally, we treated PC-9/ER (del19/T790M) and H3255/XLR cells (L858R/T790M) with erlotinib and CO-1686 in standard growth inhibition assays. Both are polyclonal populations of cells that acquired T790M in response to continuous exposure to EGFR TKIs. Again, CO-1686 was superior to erlotinib in inhibiting the growth of these cells (SI Fig. 2A, B). Collectively, the EGFR signaling and cell growth/apoptosis data indicate that CO-1686 selectively and potently affects cells harboring activating EGFR mutations as well as the T790M resistance mutation and has minimal activity in cells expressing WT EGFR. Reference: Cancer Discov. 2013 Dec;3(12):1404-15. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24065731/
In vivo activity:
Initial CO-1686 pharmacokinetics were evaluated in female NCRnu.nu mice (n=3/gp) following IV and oral delivery (SI Fig. 4A, B). 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 (Fig. 3A) and the patient-derived lung tumor xenograft (PDX) LUM1868 (Fig. 3B), while erlotinib had no inhibitory effect on tumor growth (Fig. 3A, B). The second generation EGFR TKI afatinib reduced tumor growth in NCI-H1975 EGFR T790M xenograft model (Fig. 3A) but to a lesser extent than observed with CO-1686 (P < 0.01). Anti-tumor activity of CO-1686 in the HCC827 xenograft model that expresses the exon del19 activating EGFR mutation was comparable to erlotinib and afatinib (Fig. 3C). Exploration of different oral dosing schedules demonstrated that in the NCI-H1975 model CO-1686 caused tumor regressions either given as 100 mg/kg once daily (QD) or as 50 mg/kg twice daily (BID), with no significant alterations in body weight with either dosing schedule (SI Fig. 5A, B). However, the BID CO-1686 administration schedule was statistically superior to QD day 15 post-dosing (P < 0.01) and was therefore chosen as the optimal dosing regimen (SI Fig. 5A). Reference: Cancer Discov. 2013 Dec;3(12):1404-15. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24065731/
Solvent mg/mL mM
Solubility
DMSO 43.0 77.40
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 555.55 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol:
1. Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, Dubrovskiy A, Labenski M, Zhu Z, Wang Z, Sheets M, St Martin T, Karp R, van Kalken D, Chaturvedi P, Niu D, Nacht M, Petter RC, Westlin W, Lin K, Jaw-Tsai S, Raponi M, Van Dyke T, Etter J, Weaver Z, Pao W, Singh J, Simmons AD, Harding TC, Allen A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013 Dec;3(12):1404-15. doi: 10.1158/2159-8290.CD-13-0314. Epub 2013 Sep 24. PMID: 24065731; PMCID: PMC4048995.
In vivo protocol:
1. Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, Dubrovskiy A, Labenski M, Zhu Z, Wang Z, Sheets M, St Martin T, Karp R, van Kalken D, Chaturvedi P, Niu D, Nacht M, Petter RC, Westlin W, Lin K, Jaw-Tsai S, Raponi M, Van Dyke T, Etter J, Weaver Z, Pao W, Singh J, Simmons AD, Harding TC, Allen A. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013 Dec;3(12):1404-15. doi: 10.1158/2159-8290.CD-13-0314. Epub 2013 Sep 24. PMID: 24065731; PMCID: PMC4048995.
1: He J, Huang Z, Han L, Gong Y, Xie C. Mechanisms and management of 3rd‑generation EGFR‑TKI resistance in advanced non‑small cell lung cancer (Review). Int J Oncol. 2021 Nov;59(5):90. doi: 10.3892/ijo.2021.5270. Epub 2021 Sep 24. PMID: 34558640; PMCID: PMC8562388. 2: Chuang JC, Salahudeen AA, Wakelee HA. Rociletinib, a third generation EGFR tyrosine kinase inhibitor: current data and future directions. Expert Opin Pharmacother. 2016;17(7):989-93. doi: 10.1517/14656566.2016.1162786. Epub 2016 Apr 4. PMID: 26950414. 3: Dhingra K. Rociletinib: has the TIGER lost a few of its stripes? Ann Oncol. 2016 Jun;27(6):1161-1164. doi: 10.1093/annonc/mdw140. Epub 2016 Apr 4. PMID: 27045101. 4: Tran PN, Klempner SJ. Profile of rociletinib and its potential in the treatment of non-small-cell lung cancer. Lung Cancer (Auckl). 2016 May 18;7:91-97. doi: 10.2147/LCTT.S94337. PMID: 28210165; PMCID: PMC5310702. 5: Van Der Steen N, Caparello C, Rolfo C, Pauwels P, Peters GJ, Giovannetti E. New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong? Onco Targets Ther. 2016 Oct 6;9:6065-6074. doi: 10.2147/OTT.S97644. PMID: 27785053; PMCID: PMC5063481. 6: Sequist LV, Soria JC, Goldman JW, Wakelee HA, Gadgeel SM, Varga A, Papadimitrakopoulou V, Solomon BJ, Oxnard GR, Dziadziuszko R, Aisner DL, Doebele RC, Galasso C, Garon EB, Heist RS, Logan J, Neal JW, Mendenhall MA, Nichols S, Piotrowska Z, Wozniak AJ, Raponi M, Karlovich CA, Jaw-Tsai S, Isaacson J, Despain D, Matheny SL, Rolfe L, Allen AR, Camidge DR. Rociletinib in EGFR- mutated non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1700-9. doi: 10.1056/NEJMoa1413654. PMID: 25923550. 7: Zeng F, Wang F, Zheng Z, Chen Z, Wah To KK, Zhang H, Han Q, Fu L. Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo. Acta Pharm Sin B. 2020 May;10(5):799-811. doi: 10.1016/j.apsb.2020.01.008. Epub 2020 Jan 26. PMID: 32528828; PMCID: PMC7280144. 8: Sequist LV, Rolfe L, Allen AR. Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Aug 6;373(6):578-9. doi: 10.1056/NEJMc1506831. PMID: 26244318. 9: Van Der Steen N, Rolfo C, Pauwels P, de Langen AJ, Peters GJ, Giovannetti E. Resistance Mechanisms to AZD9291 and Rociletinib-Letter. Clin Cancer Res. 2017 Jul 15;23(14):3966. doi: 10.1158/1078-0432.CCR-17-0167. PMID: 28710317. 10: He Y. Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Aug 6;373(6):578. doi: 10.1056/NEJMc1506831. PMID: 26244319. 11: Büttner R, Wolf J, Thomas RK, Sos ML. Resistance Mechanisms to AZD9291 and Rociletinib-Response. Clin Cancer Res. 2017 Jul 15;23(14):3967-3968. doi: 10.1158/1078-0432.CCR-17-0948. PMID: 28710318. 12: Yang JC, Reckamp KL, Kim YC, Novello S, Smit EF, Lee JS, Su WC, Akerley WL, Blakely CM, Groen HJM, Bazhenova L, Carcereny Costa E, Chiari R, Hsia TC, Golsorkhi T, Despain D, Shih D, Popat S, Wakelee H. Efficacy and Safety of Rociletinib Versus Chemotherapy in Patients With EGFR-Mutated NSCLC: The Results of TIGER-3, a Phase 3 Randomized Study. JTO Clin Res Rep. 2020 Oct 26;2(2):100114. doi: 10.1016/j.jtocrr.2020.100114. PMID: 34589984; PMCID: PMC8474221. 13: Surapaneni SK, Nottingham E, Mondal A, Patel N, Arthur P, Gebeyehu A, Kalvala AK, Rishi AK, Singh M. Telmisartan Facilitates the Anticancer Effects of CARP-1 Functional Mimetic and Sorafenib in Rociletinib Resistant Non-small Cell Lung Cancer. Anticancer Res. 2021 Sep;41(9):4215-4228. doi: 10.21873/anticanres.15226. Epub 2021 Sep 1. PMID: 34475041; PMCID: PMC8691118. 14: Attwa MW, Abdelhameed AS, Kadi AA. LC-MS/MS Estimation of Rociletinib Levels in Human Liver Microsomes: Application to Metabolic Stability Estimation. Drug Des Devel Ther. 2021 Sep 15;15:3915-3925. doi: 10.2147/DDDT.S321330. PMID: 34552321; PMCID: PMC8450377. 15: Ramirez J, House LK, Ratain MJ. Influence of N-acetyltransferase 2 gene polymorphisms on the in vitro metabolism of the epidermal growth factor receptor inhibitor rociletinib. Br J Clin Pharmacol. 2021 Nov;87(11):4313-4322. doi: 10.1111/bcp.14848. Epub 2021 Apr 27. PMID: 33818816. 16: Nagasaka M, Zhu VW, Lim SM, Greco M, Wu F, Ou SI. Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFR+ NSCLC. J Thorac Oncol. 2021 May;16(5):740-763. doi: 10.1016/j.jtho.2020.11.028. Epub 2020 Dec 15. PMID: 33338652. 17: Yuan S, Zou Y, Xie J. [Progress in Non-invasive Detection of EGFR Mutation in Non-small Cell Lung Cancer]. Zhongguo Fei Ai Za Zhi. 2018 Dec 20;21(12):912-917. Chinese. doi: 10.3779/j.issn.1009-3419.2018.12.09. PMID: 30591099; PMCID: PMC6318567. 18: Sequist LV, Soria JC, Camidge DR. Update to Rociletinib Data with the RECIST Confirmed Response Rate. N Engl J Med. 2016 Jun 9;374(23):2296-7. doi: 10.1056/NEJMc1602688. Epub 2016 May 11. PMID: 27195670. 19: Fawwaz M, Mishiro K, Nishii R, Sawazaki I, Shiba K, Kinuya S, Ogawa K. Synthesis and Fundamental Evaluation of Radioiodinated Rociletinib (CO-1686) as a Probe to Lung Cancer with L858R/T790M Mutations of Epidermal Growth Factor Receptor (EGFR). Molecules. 2020 Jun 24;25(12):2914. doi: 10.3390/molecules25122914. PMID: 32599930; PMCID: PMC7356761. 20: Wang S, Song Y, Liu D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017 Jan 28;385:51-54. doi: 10.1016/j.canlet.2016.11.008. Epub 2016 Nov 10. PMID: 27840244.