RO-3306
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MedKoo CAT#: 406182

CAS#: 872573-93-8

Description: RO-3306 is a CDK1 inhibitor with potential anticancer activity. Treatment of growing AML cells with RO-3306 induced G2/M-phase cell cycle arrest and apoptosis in a dose- and time-dependent manner. RO-3306 downregulated expression of the antiapoptotic proteins Bcl-2 and survivin and blocked p53-mediated induction of p21 and MDM2. RO-3306 actively enhances downstream p53 signaling to promote apoptosis.


Chemical Structure

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RO-3306
CAS# 872573-93-8

Theoretical Analysis

MedKoo Cat#: 406182
Name: RO-3306
CAS#: 872573-93-8
Chemical Formula: C18H13N3OS2
Exact Mass: 351.05
Molecular Weight: 351.44
Elemental Analysis: C, 61.52; H, 3.73; N, 11.96; O, 4.55; S, 18.24

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Ready to ship
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 750.0 Ready to ship
500.0mg USD 1450.0 Ready to ship
1.0g USD 1950.0 Ready to ship
2.0g USD 2950.0 Ready to ship
10.0g USD 7950.0 2 Weeks
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Synonym: RO3306; RO 3306; RO-3306

IUPAC/Chemical Name: 5-(6-Quinolinylmethylene)-2-[(2-thienylmethyl)amino]-4(5H)-thiazolone

InChi Key: XOLMRFUGOINFDQ-MHWRWJLKSA-N

InChi Code: InChI=1S/C18H13N3OS2/c22-17-16(24-18(21-17)20-11-14-4-2-8-23-14)10-12-5-6-15-13(9-12)3-1-7-19-15/h1-10H,11H2,(H,20,21,22)/b16-10+

SMILES Code: O=C1N=C(NCC2=CC=CS2)S/C1=C/C3=CC=C4N=CC=CC4=C3

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, not soluble in water.

Shelf Life: >5 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

Biological target: Ro-3306 is an inhibitor of CDK1, with Kis of 20 nM, 35 nM and 340 nM for CDK1, CDK1/cyclin B1 and CDK2/cyclin E, respectively.
In vitro activity: To analyze the DNA damage and repair processes during RO-3306-induced G2 arrest, this study examined whether irradiated cells undergoing prolonged G2 arrest repaired DSBs or induced damaged DNA to enter M-phase during RO-3306 treatment. Immediate discontinuation of RO-3306 treatment (10 μM) and exchanged treatment (DMSO or 2 μM) after irradiation in HL-60 cells resulted in mitotic entry and DSB levels significantly higher in M-phase cells, compared to in non-irradiated control (Fig. 4A and B). In contrast, persistent 10 μM RO-3306 treatment for 8 h after irradiation dramatically decreased DSB levels in M-phase cells compared to the immediate release of RO-3306 treatment (Fig. 4C and D). This study showed that further DNA-PK inhibition during prolonged G2 arrest delayed DNA repair and inhibited cell proliferation (supplementary Fig. 2). The clonogenic assay demonstrated that persistent treatment with RO-3306 after irradiation resulted in higher fractions of surviving HeLa cells, supporting the resistance of cells to CDK1 inhibition (Fig. 4E). These results show that even higher dose of RO-3306 induced prolonged G2 arrest, allowing irradiated cells to repair DSBs and preventing DNA damage from being carried over into M-phase. Reference: Biochem Biophys Res Commun. 2021 Apr 23;550:56-61. https://www.sciencedirect.com/science/article/pii/S0006291X21003466?via%3Dihub
In vivo activity: Subcutaneous tumor xenografts developed from HEC-1-B cells in BALB/c nude mice were successfully established individually. Consistent with the in vitro results, the tumor growth of xenograft endometrial cancer grafts was significantly blocked with the treatment of RO3306 (Figure (5A-D). As early as day 4 of the treatment, there was a extremely significant difference in tumor volume between the RO3306 treatment group and the control group (p <0.0001) (Figure 5A). At the end of the study, tumor volumes of endometrial cancer grafts in the RO3306 treatment group and the control group were 392.2 ± 24.34 and 689.8 ± 104.3mm3, respectively, with highly significant differences between the two groups (p <0.01) (Figure 5A). As to body weight, there was no significant difference between the two groups (p >0.05) (Figure 5B). The tumor weight of endometrial cancer grafts harvested at the end of the study in the RO3306 treatment group was significantly lower than that in the control group (p <0.05) (Figure 5C). These data suggested that CDK1 played an important role in the growth and proliferation of endometrial cancer cells in vivo and RO3306 can serve as its targeted inhibitor for the treatment of endometrioid endometrial cancer. Reference: J Cancer. 2021; 12(8): 2206–2215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974891/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 16.26 46.27
DMSO:PBS (pH 7.2) (1:2) 0.25 0.71
DMF 20.0 56.91

Preparing Stock Solutions

The following data is based on the product molecular weight 351.44 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.

Recalculate based on batch purity %
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. Sunada S, Saito H, Zhang D, Xu Z, Miki Y. CDK1 inhibitor controls G2/M phase transition and reverses DNA damage sensitivity. Biochem Biophys Res Commun. 2021 Apr 23;550:56-61. doi: 10.1016/j.bbrc.2021.02.117. Epub 2021 Mar 5. PMID: 33684621. 2. Kojima K, Shimanuki M, Shikami M, Andreeff M, Nakakuma H. Cyclin-dependent kinase 1 inhibitor RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis in AML. Cancer Sci. 2009 Jun;100(6):1128-36. doi: 10.1111/j.1349-7006.2009.01150.x. Epub 2009 Mar 10. PMID: 19385969; PMCID: PMC2759356. 3. Ying X, Che X, Wang J, Zou G, Yu Q, Zhang X. CDK1 serves as a novel therapeutic target for endometrioid endometrial cancer. J Cancer. 2021 Feb 22;12(8):2206-2215. doi: 10.7150/jca.51139. PMID: 33758599; PMCID: PMC7974891. 4. Czaplinski S, Hugle M, Stiehl V, Fulda S. Polo-like kinase 1 inhibition sensitizes neuroblastoma cells for vinca alkaloid-induced apoptosis. Oncotarget. 2016 Feb 23;7(8):8700-11. doi: 10.18632/oncotarget.3901. PMID: 26046302; PMCID: PMC4890998.
In vitro protocol: 1. Sunada S, Saito H, Zhang D, Xu Z, Miki Y. CDK1 inhibitor controls G2/M phase transition and reverses DNA damage sensitivity. Biochem Biophys Res Commun. 2021 Apr 23;550:56-61. doi: 10.1016/j.bbrc.2021.02.117. Epub 2021 Mar 5. PMID: 33684621. 2. Kojima K, Shimanuki M, Shikami M, Andreeff M, Nakakuma H. Cyclin-dependent kinase 1 inhibitor RO-3306 enhances p53-mediated Bax activation and mitochondrial apoptosis in AML. Cancer Sci. 2009 Jun;100(6):1128-36. doi: 10.1111/j.1349-7006.2009.01150.x. Epub 2009 Mar 10. PMID: 19385969; PMCID: PMC2759356.
In vivo protocol: 1. Ying X, Che X, Wang J, Zou G, Yu Q, Zhang X. CDK1 serves as a novel therapeutic target for endometrioid endometrial cancer. J Cancer. 2021 Feb 22;12(8):2206-2215. doi: 10.7150/jca.51139. PMID: 33758599; PMCID: PMC7974891. 2. Czaplinski S, Hugle M, Stiehl V, Fulda S. Polo-like kinase 1 inhibition sensitizes neuroblastoma cells for vinca alkaloid-induced apoptosis. Oncotarget. 2016 Feb 23;7(8):8700-11. doi: 10.18632/oncotarget.3901. PMID: 26046302; PMCID: PMC4890998.

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1: Pantelias A, Karachristou I, Georgakilas AG, Terzoudi GI. Interphase Cytogenetic Analysis of Micronucleated and Multinucleated Cells Supports the Premature Chromosome Condensation Hypothesis as the Mechanistic Origin of Chromothripsis. Cancers (Basel). 2019 Aug 6;11(8). pii: E1123. doi: 10.3390/cancers11081123. PubMed PMID: 31390832; PubMed Central PMCID: PMC6721583.

2: Swadi RR, Sampat K, Herrmann A, Losty PD, See V, Moss DJ. CDK inhibitors reduce cell proliferation and reverse hypoxia-induced metastasis of neuroblastoma tumours in a chick embryo model. Sci Rep. 2019 Jun 24;9(1):9136. doi: 10.1038/s41598-019-45571-8. PubMed PMID: 31235824; PubMed Central PMCID: PMC6591221.

3: Subedar OD, Chiu LLY, Waldman SD. Cell Cycle Synchronization of Primary Articular Chondrocytes Enhances Chondrogenesis. Cartilage. 2019 Apr 11:1947603519841677. doi: 10.1177/1947603519841677. [Epub ahead of print] PubMed PMID: 30971093.

4: Gregg T, Sdao SM, Dhillon RS, Rensvold JW, Lewandowski SL, Pagliarini DJ, Denu JM, Merrins MJ. Obesity-dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic β-cells. J Biol Chem. 2019 Mar 22;294(12):4656-4666. doi: 10.1074/jbc.RA118.006085. Epub 2019 Jan 30. PubMed PMID: 30700550; PubMed Central PMCID: PMC6433064.

5: Okumura D, Hagino M, Yamagishi A, Kaibori Y, Munira S, Saito Y, Nakayama Y. Inhibitors of the VEGF Receptor Suppress HeLa S3 Cell Proliferation via Misalignment of Chromosomes and Rotation of the Mitotic Spindle, Causing a Delay in M-Phase Progression. Int J Mol Sci. 2018 Dec 12;19(12). pii: E4014. doi: 10.3390/ijms19124014. PubMed PMID: 30545129; PubMed Central PMCID: PMC6320846.

6: de Macedo MP, Glanzner WG, Rissi VB, Gutierrez K, Currin L, Baldassarre H, Bordignon V. A fast and reliable protocol for activation of porcine oocytes. Theriogenology. 2019 Jan 1;123:22-29. doi: 10.1016/j.theriogenology.2018.09.021. Epub 2018 Sep 24. PubMed PMID: 30273737.

7: Jorda R, Hendrychová D, Voller J, Řezníčková E, Gucký T, Kryštof V. How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases? J Med Chem. 2018 Oct 25;61(20):9105-9120. doi: 10.1021/acs.jmedchem.8b00049. Epub 2018 Oct 5. PubMed PMID: 30234987.

8: Santos AJM, Boucrot E. Probing Endocytosis During the Cell Cycle with Minimal Experimental Perturbation. Methods Mol Biol. 2018;1847:23-35. doi: 10.1007/978-1-4939-8719-1_3. Erratum in: Methods Mol Biol. 2018;1847:E1. PubMed PMID: 30129007.

9: Wu CX, Wang XQ, Chok SH, Man K, Tsang SHY, Chan ACY, Ma KW, Xia W, Cheung TT. Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics. 2018 Jun 13;8(14):3737-3750. doi: 10.7150/thno.25487. eCollection 2018. PubMed PMID: 30083256; PubMed Central PMCID: PMC6071527.

10: Prevo R, Pirovano G, Puliyadi R, Herbert KJ, Rodriguez-Berriguete G, O'Docherty A, Greaves W, McKenna WG, Higgins GS. CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner. Cell Cycle. 2018;17(12):1513-1523. doi: 10.1080/15384101.2018.1491236. Epub 2018 Jul 25. PubMed PMID: 30045664; PubMed Central PMCID: PMC6132956.

11: Zhang P, Kawakami H, Liu W, Zeng X, Strebhardt K, Tao K, Huang S, Sinicrope FA. Targeting CDK1 and MEK/ERK Overcomes Apoptotic Resistance in BRAF-Mutant Human Colorectal Cancer. Mol Cancer Res. 2018 Mar;16(3):378-389. doi: 10.1158/1541-7786.MCR-17-0404. Epub 2017 Dec 12. PubMed PMID: 29233910.

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13: Kudou K, Komatsu T, Nogami J, Maehara K, Harada A, Saeki H, Oki E, Maehara Y, Ohkawa Y. The requirement of Mettl3-promoted MyoD mRNA maintenance in proliferative myoblasts for skeletal muscle differentiation. Open Biol. 2017 Sep;7(9). pii: 170119. doi: 10.1098/rsob.170119. PubMed PMID: 28878038; PubMed Central PMCID: PMC5627051.

14: Gardner NJ, Gillespie PJ, Carrington JT, Shanks EJ, McElroy SP, Haagensen EJ, Frearson JA, Woodland A, Blow JJ. The High-Affinity Interaction between ORC and DNA that Is Required for Replication Licensing Is Inhibited by 2-Arylquinolin-4-Amines. Cell Chem Biol. 2017 Aug 17;24(8):981-992.e4. doi: 10.1016/j.chembiol.2017.06.019. Epub 2017 Aug 3. PubMed PMID: 28781123; PubMed Central PMCID: PMC5563080.

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17: Müllers E, Silva Cascales H, Burdova K, Macurek L, Lindqvist A. Residual Cdk1/2 activity after DNA damage promotes senescence. Aging Cell. 2017 Jun;16(3):575-584. doi: 10.1111/acel.12588. Epub 2017 Mar 26. PubMed PMID: 28345297; PubMed Central PMCID: PMC5418196.

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19: Wang XQ, Lo CM, Chen L, Ngan ES, Xu A, Poon RY. CDK1-PDK1-PI3K/Akt signaling pathway regulates embryonic and induced pluripotency. Cell Death Differ. 2017 Jan;24(1):38-48. doi: 10.1038/cdd.2016.84. Epub 2016 Sep 16. PubMed PMID: 27636107; PubMed Central PMCID: PMC5260505.

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RO-3306

10.0mg / USD 90.0


Additional Information