GDC-0575 (also called ARRY-575, RG7741) is a novel, potent and selective inhibitor of CHK1 (Check point kinases) which specifically binds to and inhibits CHK1 with an IC50 of 1.2 nM. This enables tumor cells to escape the cell cycle arrest in the S and G2/M phases that is dependent on CHK1, allowing the cells to undergo DNA repair before going through mitosis. In response to DNA damage, the ATP-dependent serine-threonine kinase CHK1 phosphorylates the cdc25 phosphatases. As a result, CHK1 inhibition may make tumor cells more vulnerable to the damaging effects of some chemotherapy drugs on DNA.

Physicochemical Properties

Molecular Formula	C16H20BRN5O
Molecular Weight	378.2669
Exact Mass	377.09
Elemental Analysis	C, 50.80; H, 5.33; Br, 21.12; N, 18.51; O, 4.23
CAS #	1196541-47-5
Related CAS #	GDC-0575 dihydrochloride;1657014-42-0;GDC0575 hydrochloride;1196504-54-7
PubChem CID	46917793
Appearance	Light yellow to yellow solid powder
LogP	1.4
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	3
Heavy Atom Count	23
Complexity	460
Defined Atom Stereocenter Count	1
SMILES	C1C[C@H](CN(C1)C2=C3C(=CNC3=NC=C2Br)NC(=O)C4CC4)N
InChi Key	BAZRWWGASYWYGB-SNVBAGLBSA-N
InChi Code	InChI=1S/C16H20BrN5O/c17-11-6-19-15-13(14(11)22-5-1-2-10(18)8-22)12(7-20-15)21-16(23)9-3-4-9/h6-7,9-10H,1-5,8,18H2,(H,19,20)(H,21,23)/t10-/m1/s1
Chemical Name	N-[4-[(3R)-3-aminopiperidin-1-yl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]cyclopropanecarboxamide
Synonyms	ARRY-575; ARRY-575; ARRY575; RG7741; RG-7741; RG 7741; GDC-0575; GDC 0575; GDC0575; AK 687476; AK-687476; AK687476
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	Chk1 (IC50 = 1.2 nM)
ln Vitro	GDC-0575 exhibits notably greater potency than V158411, LY2603618, and MK-8776 in inducing DNA damage, replication stress, and cell death in a panel of melanoma cell lines[1]. GDC-0575 exacerbates DNA double-strand breaks, causes apoptosis in STS cells, and nullifies DNA damage-induced S and G2–M checkpoints. Gemcitabine and GDC-0575 have an additive or synergistic effect[2]. When combined with AraC, the CHK1 inhibitor GDC-0575 improves the ex vivo death of primary acute myeloid leukemia cells by triggering apoptosis[3].
ln Vivo	GDC-0575 is effective when used alone at a dose of 25 mg/kg, but the higher dosage of the medication improves efficacy. The D20 and C002 xenografts are successfully prevented from growing tumors by GDC-0575, and this effect lasts for at least ten days following the last dose[1].
Enzyme Assay	GDC-0575, also known as ARRY-575 or RG7741, is a novel, strong, and selective inhibitor of CHK1 that binds to it specifically and inhibits it with an IC50 of 1.2 nM.
Cell Assay	AML cell lines are plated in triplicate in 96-well plates at a density of 1×104 cells/well, and are then exposed to various treatment scenarios. The XTT Cell Proliferation Kit II is used to measure cell proliferation following a 24-hour incubation period with GDC-0575[3].
Animal Protocol	Mice: Woman in the nude The hind flank of BALB/c mice receives a subcutaneous injection of 2-3×106 melanoma cells in Matrigel. Mice with tumors up to 100 mm3 are given GDC-0575 (25 mg/kg, 50 mg/kg) or vehicle (0.5% w/v methylcellulose and 0.2% v/v Tween 80) orally. Treatment is given for three cycles, one of which consists of three treatment days in a row followed by four days off. Using calipers, the size of the tumor is measured three times a week. Animals are killed when the treatment is stopped for up to six weeks or when the tumor is larger than one centimeter in diameter [1]..
References	[1]. Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo. Clin Cancer Res. 2018 Mar 13. doi: 10.1158/1078-0432.CCR-17-2701. [2]. CHK1 inhibition in soft-tissue sarcomas: biological and clinical implications. Ann Oncol. 2018 Apr 1;29(4):1023-1029. [3]. The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia. Nat Commun. 2017 Nov 22;8(1):1679

Solubility Data

Solubility (In Vitro)

DMSO: ~75 mg/mL (~198 mM) Water: <1mg/mL Ethanol: ~5 mg/mL (~13.2 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.6436 mL	13.2181 mL	26.4361 mL
	5 mM	0.5287 mL	2.6436 mL	5.2872 mL
	10 mM	0.2644 mL	1.3218 mL	2.6436 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.