ARS-1620 | CAS#1698055-85-4 | KRAS-G12C inhibitor

MedKoo Cat#: 407924 | Name: ARS-1620

Description:

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

ARS-1620 is an atropisomeric selective KRAS-G12C inhibitor with desirable pharmacokinetics. ARS-1620 is a covalent compound with high potency and selectivity for KRAS-G12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. ARS-1620 represents a new generation of KRAS-G12C-specific inhibitors with promising therapeutic potential.

Chemical Structure

ARS-1620

CAS#1698055-85-4

Theoretical Analysis

MedKoo Cat#: 407924

Name: ARS-1620

CAS#: 1698055-85-4

Chemical Formula: C21H17ClF2N4O2

Exact Mass: 430.1008

Molecular Weight: 430.84

Elemental Analysis: C, 58.54; H, 3.98; Cl, 8.23; F, 8.82; N, 13.00; O, 7.43

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,850.00	Ready to ship
1g	USD 4,250.00	Ready to ship

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Related CAS #

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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

Appearance

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

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;

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T20D05P13

QC Data

View QC data: current batch, Lot#T20D05P13

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

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
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:

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.