CH6953755 | CAS#2055918-71-1 | YES1 kinase inhibitor

MedKoo Cat#: 462198 | Name: CH6953755

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Description:

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

CH6953755 is a potent, orally active and selective YES1 kinase (a member of the SRC family) inhibitor. CH6953755 inhibits YES1 kinase, leading to antitumor activity against YES1 Gene -amplified cancers in vitro and in vivo.

Chemical Structure

CH6953755

CAS#2055918-71-1

Theoretical Analysis

MedKoo Cat#: 462198

Name: CH6953755

CAS#: 2055918-71-1

Chemical Formula: C26H24F2N6O4S

Exact Mass: 554.1548

Molecular Weight: 554.57

Elemental Analysis: Elemental Analysis: C, 56.31; H, 4.36; F, 6.85; N, 15.15; O, 11.54; S, 5.78

Price and Availability

Size	Price	Availability	Quantity
5mg	USD 450.00	2 Weeks
10mg	USD 750.00	2 Weeks

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Synonym

CH6953755; CH-6953755; CH 6953755;

IUPAC/Chemical Name

N-(2-(5-amino-1-(6-(2,6-difluorophenoxy)-4-methylpyridin-3-yl)-1H-pyrazole-4-carbonyl)-5-methyl-3a,7a-dihydro-1H-indol-6-yl)methanesulfonamide

InChi Key

NQAWLJCOACFOBR-UHFFFAOYSA-N

InChi Code

InChI=1S/C26H24F2N6O4S/c1-13-7-15-9-21(32-20(15)10-19(13)33-39(3,36)37)24(35)16-11-31-34(26(16)29)22-12-30-23(8-14(22)2)38-25-17(27)5-4-6-18(25)28/h4-12,15,20,32-33H,29H2,1-3H3

SMILES Code

CC1=CC(C=C(C(C2=C(N)N(C3=C(C)C=C(OC4=C(F)C=CC=C4F)N=C3)N=C2)=O)N5)C5C=C1NS(=O)(C)=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

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Product Data

Product Data

Instruction

View handling instruction

Biological target:

CH6953755 is a potent, orally active and selective YES1 kinase (a member of the SRC family) inhibitor with an IC50 of 1.8 nM.

In vitro activity:

CH6953755 was tested against a panel of 66 cancer cell lines, seven of which had YES1 amplification. YES1-amplified cancer cell lines showed higher sensitivity to CH6953755 than non-YES1–amplified cancer cell lines (Fig. 3A; Supplementary Table S3). CH6953755 prevented the autophosphorylation at Tyr426 of YES1 that upregulates enzymatic activity in KYSE70 cells harboring YES1 amplification (Fig. 3B). CH6953755 cytotoxicity was checked to see if it was the result of YES1 inhibition in YES1-amplified cancer cell lines using the commonly used chemical–genetic approach of engineering an inhibitor-resistant mutant of YES1. From YES1-amplified KYSE70 and OACP4 C, and YES1 nonamplified K562 cell lines, clones stably transduced with a lentiviral vector expressing YES1-WT or mutant T348I, a so-called gatekeeper mutation (YES1-GK) that had a point mutation at the binding site with CH6953755 and was expected to be resistant to CH6953755. In KYSE70 cells expressing YES1-GK (KYSE70_YES1-GK), phosphorylation at Tyr426 was not suppressed by CH6953755 treatment, unlike in KYSE70 cells expressing YES1-WT (KYSE70_YES1-WT; Fig. 3C). As we expected, the two cell lines expressing YES1-GK with amplified YES1 gene became resistant to CH6953755, while this was not the case with the line without amplified YES1 (Fig. 3D). Similar results were found with dasatinib (Supplementary Fig. S4). These results indicated that YES1 kinase inhibition inhibited the cell growth of YES1-amplified cancer cell lines. Reference: Cancer Res. 2019 Nov 15;79(22):5734-5745. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=31391186

In vivo activity:

To confirm whether YES1 inhibition led to antitumor activity in vivo, as well as cell growth inhibition in vitro, first the in vivo efficacy of YES1 inhibitor CH6953755 was evaluated in a Rat-2_YES1 xenograft mouse model. After oral treatment of CH6953755 at 60 mg/kg, the antitumor activity (Fig. 4A) was accompanied with phospho-Tyr426 YES1 suppression in xenograft tumors (Fig. 4B). Next, native cancer cell lines harboring YES1 gene amplification were utilized. Consistent with the findings in the Rat-2_YES1 model, CH6953755 showed antitumor activity against xenograft models with YES1 amplification, such as KYSE70 [copy number = 9.9, maximum tumor growth inhibition (TGI) 90% at the MTD] and RERF-LC-AI (copy number = 5.1, maximum TGI 93% at the MTD; Fig. 4C). In contrast, CH6953755 did not show antitumor activity against xenograft models with no YES1 amplification, such as ACHN (copy number = 1.8, maximum TGI 13% at the MTD) and HARA (copy number = 2.7, maximum TGI 13% at the MTD; Fig. 4D). These data were in line with the in vitro observations. We also tested dasatinib against a YES1-amplified KYSE70 model. Because its toxicity limits the dose, dasatinib showed moderate efficacy (maximum TGI 41% at the MTD; Supplementary Fig. S6). Then we evaluated the suppression of YES1 signaling in tumor tissues by conducting Western blotting 24 hours after the last administration of daily dosing. The blots demonstrated that CH6953755 suppressed phospho-Tyr426 YES1 in a dose-dependent manner (Fig. 4E). These results suggest that YES1 kinase inhibition by CH6953755 leads to selective antitumor activity against YES1-amplified cancers both in vitro and in vivo, and YES1 kinase plays a crucial role in YES1-amplified cancers. Reference: Cancer Res. 2019 Nov 15;79(22):5734-5745. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=31391186

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	125.0	226.22

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 554.57 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:

In vitro protocol:

1. Hamanaka N, Nakanishi Y, Mizuno T, Horiguchi-Takei K, Akiyama N, Tanimura H, Hasegawa M, Satoh Y, Tachibana Y, Fujii T, Sakata K, Ogasawara K, Ebiike H, Koyano H, Sato H, Ishii N, Mio T. YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification. Cancer Res. 2019 Nov 15;79(22):5734-5745. doi: 10.1158/0008-5472.CAN-18-3376. Epub 2019 Aug 7. PMID: 31391186.

In vivo protocol:

1: Hamanaka N, Nakanishi Y, Mizuno T, et al. YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification. Cancer Res. 2019;79(22):5734-5745. doi:10.1158/0008-5472.CAN-18-3376

Description:

Chemical Structure

Theoretical Analysis

Price and Availability

Preparing Stock Solutions

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