ARS-1620

• CAT Number: I012099
• CAS Number: 1698055-85-4
• Molecular Formula: C21H17ClF2N4O2
• Molecular Weight: 430.1
• Purity: ≥95%
• Synonyms: ARS-1620,ARS 1620,ARS1620
• Target: GPCR/G Protein

ARS-1620 (CAT: I012099) is a covalent compound known for its high potency and selectivity as a KRAS-G12C inhibitor. It has demonstrated the ability to induce tumor regression in patient-derived tumor models. As an atropisomers selective inhibitor, ARS-1620 shows desirable pharmacokinetic properties. In vivo, studies have highlighted the significant KRAS dependency in living organisms compared to 2D-monolayer cell culture. ARS-1620 achieves rapid and sustained target occupancy, leading to tumor regression. This compound is a valuable pharmacological tool to investigate KRAS biology in vivo and represents a new generation of promising KRAS-G12C-specific inhibitors with potential therapeutic applications.

Reference

1. Cell. 2018 Jan 25;172(3):578-589.e17. doi: 10.1016/j.cell.2018.01.006.

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

Janes MR(1), Zhang J(1), Li LS(1), Hansen R(1), Peters U(1), Guo X(1), Chen Y(1),
Babbar A(1), Firdaus SJ(1), Darjania L(1), Feng J(1), Chen JH(1), Li S(1), Li
S(1), Long YO(1), Thach C(1), Liu Y(1), Zarieh A(1), Ely T(1), Kucharski JM(1),
Kessler LV(1), Wu T(1), Yu K(1), Wang Y(1), Yao Y(1), Deng X(1), Zarrinkar PP(1),
Brehmer D(2), Dhanak D(3), Lorenzi MV(3), Hu-Lowe D(1), Patricelli MP(1), Ren
P(4), Liu Y(5).

Author information:
(1)Wellspring Biosciences, San Diego, CA, USA.
(2)Oncology Discovery, Janssen Research & Development, Beerse, Belgium.
(3)Janssen Research & Development, Spring House, PA, USA.
(4)Wellspring Biosciences, San Diego, CA, USA; Kura Oncology, San Diego, CA, USA.
(5)Wellspring Biosciences, San Diego, CA, USA; Kura Oncology, San Diego, CA, USA.
Electronic address: .

KRASG12C 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 KRASG12C
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; however, it is uncertain whether this
approach would translate to in vivo. Here, we describe structure-based design and
identification of ARS-1620, a covalent compound with high potency and selectivity
for KRASG12C. 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. This study provides in vivo evidence that mutant KRAS can be
selectively targeted and reveals ARS-1620 as representing a new generation of
KRASG12C-specific inhibitors with promising therapeutic potential.