Synonym
ARS-1620; ARS 1620; ARS1620;
IUPAC/Chemical Name
(S)-1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one
InChi Key
ZRPZPNYZFSJUPA-UHFFFAOYSA-N
InChi Code
InChI=1S/C21H17ClF2N4O2/c1-2-16(30)27-6-8-28(9-7-27)21-12-10-13(22)17(19(24)20(12)25-11-26-21)18-14(23)4-3-5-15(18)29/h2-5,10-11,29H,1,6-9H2
SMILES Code
C=CC(N1CCN(C2=C3C=C(Cl)[C@@]([C@@]4=C(O)C=CC=C4F)=C(F)C3=NC=N2)CC1)=O
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
Shelf Life
>3 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
KRAS-G12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS-G12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro;
Biological target:
ARS-1620 is an atropisomeric selective KRASG12C inhibitor that exhibits complete growth suppression of p.G12C cell lines (IC50 = 150 nM).
In vitro activity:
For this purpose, the KRAS-mutant specific inhibitor ARS-1620, a selective covalent inhibitor that specifically blocks the KRASG12C mutant protein, was tested. KRAS-G12C mutations account for 40% of the KRAS mutations in NSCLC. H23 and H358 cells, which harbor KRAS-G12C mutations, showed a partial inhibition of cell proliferation when they were treated with ARS-1620 as single agent (Fig. 6A). Signaling pathway analysis revealed that ARS-1620 produced not only a robust inhibition of ERK phosphorylation, but also a reduction in S6 phosphorylation. As expected, ARS-1620 selectively inhibited the growth of cells harboring KRAS-G12C mutations but no inhibition in cell proliferation or signaling were observed in either cells harboring a KRASG12S mutation or KRAS wild-type cells (Fig. 6F, fig. S7D and S7E), whereas the KRAS-G12S mutant cells responded to KRAS knock-down (fig. S7F). H1792 cells, which also carry a KRAS-G12C mutation, responded weakly to single treatment with ARS-1620. It has been described that cell adherence can attenuate the KRAS-dependency and therefore the response to ARS-1620 in KRASG12C mutant cells. Consistent with this, it was observed that all KRAS-G12C cell lines that were tested, including H1792 cells, showed sensitivity to ARS-1620 when they were grown in suspension as spheroid cultures (fig. S7L). Next, an extended panel of cells carrying KRAS-G12C mutations was used to test the combination of KRAS, IGF1R, and mTOR inhibitors
Reference: Sci Transl Med. 2019 Sep 18; 11(510): eaaw7999. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764843/
In vivo activity:
The effects of ARS-1620 were initially evaluated in linsitinib and everolimus in mouse xenografts of human KRAS-G12C lung adenocarcinoma cell lines. In HCC44 xenografts, the treatment with ARS-1620 produced a partial inhibition of tumor growth. H358 and H1373 xenografts were more sensitive to ARS-1620 treatment. However, as shown in the waterfall plot (Fig. 7B), one H358 tumor treated with ARS-1620 alone was resistant and grew to the same extent as the vehicle-treated tumors. In contrast, all H1373 tumors responded to ARS-1620 but started to progress in the third week of treatment. These results suggest that although treatment with ARS-1620 alone can produce tumor regression,. Next, it was aimed to investigate the efficacy of the combinations in an immunocompetent mouse model of aggressive KRAS-mutant lung adenocarcinoma. In contrast to the parental cells, NRAS knockout cells (3LL ΔNRAS) exhibited a strong sensitivity to ARS-1620, which correlated with markedly improved inhibition of pathways downstream of RAS (Fig. 7C and 7D). Consistent with the results obtained in human NSCLC cell lines. Moreover, treatments with ARS-1620 resulted in a stronger induction of apoptosis in 3LL ΔNRAS cells, whereas in the parental 3LL cells only the treatments with trametinib induced apoptosis (Fig. 7F).
Reference: Sci Transl Med. 2019 Sep 18; 11(510): eaaw7999. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764843/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
70.0 |
162.47 |
|
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
430.84
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.
| 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:
1. Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E, Romero-Clavijo P, Herbert E, Horswell S, Li LS, Janes MR, Hancock DC, Downward J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019 Sep 18;11(510):eaaw7999. doi: 10.1126/scitranslmed.aaw7999. PMID: 31534020; PMCID: PMC6764843. 2. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, Hong CB, Corcoran RB. Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition. Clin Cancer Res. 2020 Apr 1;26(7):1633-1643. doi: 10.1158/1078-0432.CCR-19-3523. Epub 2019 Nov 27. PMID: 31776128; PMCID: PMC7124991.
3. Shankar S, Tien JC, Siebenaler RF, Chugh S, Dommeti VL, Zelenka-Wang S, Wang XM, Apel IJ, Waninger J, Eyunni S, Xu A, Mody M, Goodrum A, Zhang Y, Tesmer JJ, Mannan R, Cao X, Vats P, Pitchiaya S, Ellison SJ, Shi J, Kumar-Sinha C, Crawford HC, Chinnaiyan AM. An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development. Nat Commun. 2020 Jun 4;11(1):2817. doi: 10.1038/s41467-020-16309-2. PMID: 32499547; PMCID: PMC7272436.
In vitro protocol:
1. Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E, Romero-Clavijo P, Herbert E, Horswell S, Li LS, Janes MR, Hancock DC, Downward J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019 Sep 18;11(510):eaaw7999. doi: 10.1126/scitranslmed.aaw7999. PMID: 31534020; PMCID: PMC6764843. 2. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, Hong CB, Corcoran RB. Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition. Clin Cancer Res. 2020 Apr 1;26(7):1633-1643. doi: 10.1158/1078-0432.CCR-19-3523. Epub 2019 Nov 27. PMID: 31776128; PMCID: PMC7124991.
In vivo protocol:
1. Shankar S, Tien JC, Siebenaler RF, Chugh S, Dommeti VL, Zelenka-Wang S, Wang XM, Apel IJ, Waninger J, Eyunni S, Xu A, Mody M, Goodrum A, Zhang Y, Tesmer JJ, Mannan R, Cao X, Vats P, Pitchiaya S, Ellison SJ, Shi J, Kumar-Sinha C, Crawford HC, Chinnaiyan AM. An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development. Nat Commun. 2020 Jun 4;11(1):2817. doi: 10.1038/s41467-020-16309-2. PMID: 32499547; PMCID: PMC7272436.
2. Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E, Romero-Clavijo P, Herbert E, Horswell S, Li LS, Janes MR, Hancock DC, Downward J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019 Sep 18;11(510):eaaw7999. doi: 10.1126/scitranslmed.aaw7999. PMID: 31534020; PMCID: PMC6764843
1: Hansen R, Peters U, Babbar A, Chen Y, Feng J, Janes MR, Li LS, Ren P, Liu Y,
Zarrinkar PP. The reactivity-driven biochemical mechanism of covalent KRAS(G12C)
inhibitors. Nat Struct Mol Biol. 2018 May 14. doi: 10.1038/s41594-018-0061-5.
[Epub ahead of print] PubMed PMID: 29760531.
2: Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, Chen Y, Babbar A, Firdaus
SJ, Darjania L, Feng J, Chen JH, Li S, Li S, Long YO, Thach C, Liu Y, Zarieh A,
Ely T, Kucharski JM, Kessler LV, Wu T, Yu K, Wang Y, Yao Y, Deng X, Zarrinkar PP,
Brehmer D, Dhanak D, Lorenzi MV, Hu-Lowe D, Patricelli MP, Ren P, Liu Y.
Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell. 2018
Jan 25;172(3):578-589.e17. doi: 10.1016/j.cell.2018.01.006. PubMed PMID:
29373830.
