GGTI-298 free base
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MedKoo CAT#: 206801

CAS#: 180977-44-0 (free base)

Description: GGTI-298 is a potent geranylgeranyltransferase-I (GGTase-I) inhibitor with potential antitumor actrivity. GGTI-298 disrupts MAP kinase activation and G(1)-S transition in Ki-Ras-overexpressing transformed adrenocortical cells. GGTI-298 induces hypophosphorylation of retinoblastoma and partner switching of cyclin-dependent kinase inhibitors. A potential mechanism for GGTI-298 antitumor activity. GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells.

Chemical Structure

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GGTI-298 free base
CAS# 180977-44-0 (free base)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206801
Name: GGTI-298 free base
CAS#: 180977-44-0 (free base)
Chemical Formula: C27H33N3O3S
Exact Mass: 479.22
Molecular Weight: 479.634
Elemental Analysis: C, 67.61; H, 6.93; N, 8.76; O, 10.01; S, 6.69

Price and Availability

Size Price Availability Quantity
100mg USD 950 2 weeks
200mg USD 1650 2 weeks
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Related CAS #: 180977-44-0 (free base)   1217457-86-7 (TFA)   205590-41-6 (HCl)  

Synonym: GGTI298; GGTI 298; GGTI-298.

IUPAC/Chemical Name: (S)-methyl 2-(4-(((R)-2-amino-3-mercaptopropyl)amino)-2-(naphthalen-1-yl)benzamido)-4-methylpentanoate

InChi Key: XVWPFYDMUFBHBF-CLOONOSVSA-N

InChi Code: InChI=1S/C27H33N3O3S/c1-17(2)13-25(27(32)33-3)30-26(31)23-12-11-20(29-15-19(28)16-34)14-24(23)22-10-6-8-18-7-4-5-9-21(18)22/h4-12,14,17,19,25,29,34H,13,15-16,28H2,1-3H3,(H,30,31)/t19-,25+/m1/s1

SMILES Code: CC(C)C[C@H](NC(C1=CC=C(NC[C@@H](N)CS)C=C1C2=C3C=CC=CC3=CC=C2)=O)C(OC)=O

Appearance: white 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 in water

Shelf Life: >2 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:
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Biological target: GGTI298 is a CAAZ peptidomimetic geranylgeranyltransferase I (GGTase I) inhibitor, strongly inhibiting the processing of geranylgeranylated Rap1A with little effect on processing of farnesylated Ha-Ras, with IC50 values of 3 and > 20 μM in vivo, respectively.
In vitro activity: GGTI-298 was previously shown to induce G1 arrest and apoptosis in A549 lung cancer cells. The effects of GGTI-298 were examined on cell growth and induction of apoptosis in a panel of human NSCLC cell lines. After a 3-day exposure, GGTI-298 exhibited concentration-dependent effects on decreasing the cell numbers of 6 NSCLC cell lines tested, with IC50s ranging between 2 to 10 μM, indicating that GGTI-298 effectively inhibits the growth of human NSCLC cells. Among these cell lines, the H226 cell line was the least sensitive to GGTI-298 (Fig. 1A). By Annexin V staining, an increase was detected in the number of apoptotic cells as well as necrotic cells in the four tested cell lines (i.e., A549, Calu-1, H157 and H226) exposed to GGTI-298 for 48 h, demonstrating that GGTI-298 induces cell death, particularly apoptotic cell death. Similarly, the least apoptotic cells were detected in H226 cells treated with GGTI-298, indicating that H226 cells were less sensitive to GGTI-298-induced apoptosis (Fig. 1B). In agreement with previous reports, it was found that GGTI-298 also induced G1 arrest in these NSCLC cell lines (data not shown). Reference: Mol Cancer. 2010 Jan 29;9:23. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20113484/
In vivo activity: Eight mice per group were treated with either 0.9% saline (Control) or GGTI-298 (1.16 mg/kg) at day 3 post cell transplantation, to determine the effects of in both the subcutaneous and intraoessous models. Tumor growth under the dorsal skin and in the tibiae were monitored by BLI twice per week from day 3 (before drug administration) to day 35 (Figure 5A). The dorsal skin and the tibia samples were harvested on day 35 post cell transplantation to double check the presence of the Luc-G33 cells and the histological changes of the cells if any. GGTI-298 single treatment resulted in no significant reduction in tumor cell viability in the subcutaneous model (Figure 5B). Reference: Connect Tissue Res. 2015 Nov;56(6):493-503. https://www.tandfonline.com/doi/full/10.3109/03008207.2015.1075519

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 208.49

Preparing Stock Solutions

The following data is based on the product molecular weight 479.63 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. Chen S, Fu L, Raja SM, Yue P, Khuri FR, Sun SY. Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis. Mol Cancer. 2010 Jan 29;9:23. doi: 10.1186/1476-4598-9-23. PMID: 20113484; PMCID: PMC2824632. 2. Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J Biol Chem. 1997 Oct 24;272(43):27224-9. doi: 10.1074/jbc.272.43.27224. PMID: 9341167. 3. Lau CP, Wong KC, Huang L, Li G, Tsui SK, Kumta SM. A mouse model of luciferase-transfected stromal cells of giant cell tumor of bone. Connect Tissue Res. 2015 Nov;56(6):493-503. doi: 10.3109/03008207.2015.1075519. Epub 2015 Sep 1. PMID: 26327464.
In vitro protocol: 1. Chen S, Fu L, Raja SM, Yue P, Khuri FR, Sun SY. Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis. Mol Cancer. 2010 Jan 29;9:23. doi: 10.1186/1476-4598-9-23. PMID: 20113484; PMCID: PMC2824632. 2. Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J Biol Chem. 1997 Oct 24;272(43):27224-9. doi: 10.1074/jbc.272.43.27224. PMID: 9341167.
In vivo protocol: 1. Lau CP, Wong KC, Huang L, Li G, Tsui SK, Kumta SM. A mouse model of luciferase-transfected stromal cells of giant cell tumor of bone. Connect Tissue Res. 2015 Nov;56(6):493-503. doi: 10.3109/03008207.2015.1075519. Epub 2015 Sep 1. PMID: 26327464.

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1: Chu UB, Duellman T, Weaver SJ, Tao Y, Yang J. Endothelial protective genes induced by statin are mimicked by ERK5 activation as triggered by a drug combination of FTI-277 and GGTI-298. Biochim Biophys Acta. 2015 Jul;1850(7):1415-25. doi: 10.1016/j.bbagen.2015.03.011. PubMed PMID: 25829196; PubMed Central PMCID: PMC4465438.

2: Allal C, Pradines A, Hamilton AD, Sebti SM, Favre G. Farnesylated RhoB prevents cell cycle arrest and actin cytoskeleton disruption caused by the geranylgeranyltransferase I inhibitor GGTI-298. Cell Cycle. 2002 Nov-Dec;1(6):430-7. PubMed PMID: 12548020.

3: Lau CP, Wong KC, Huang L, Li G, Tsui SK, Kumta SM. A mouse model of luciferase-transfected stromal cells of giant cell tumor of bone. Connect Tissue Res. 2015 Nov;56(6):493-503. doi: 10.3109/03008207.2015.1075519. PubMed PMID: 26327464.

4: Mazet JL, Padieu M, Osman H, Maume G, Mailliet P, Dereu N, Hamilton AD, Lavelle F, Sebti SM, Maume BF. Combination of the novel farnesyltransferase inhibitor RPR130401 and the geranylgeranyltransferase-1 inhibitor GGTI-298 disrupts MAP kinase activation and G(1)-S transition in Ki-Ras-overexpressing transformed adrenocortical cells. FEBS Lett. 1999 Oct 29;460(2):235-40. PubMed PMID: 10544242.

5: Coxon FP, Helfrich MH, Van't Hof R, Sebti S, Ralston SH, Hamilton A, Rogers MJ. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res. 2000 Aug;15(8):1467-76. PubMed PMID: 10934645.

6: Edwards DC, McKinnon KM, Fenizia C, Jung KJ, Brady JN, Pise-Masison CA. Inhibition of geranylgeranyl transferase-I decreases cell viability of HTLV-1-transformed cells. Viruses. 2011 Oct;3(10):1815-35. doi: 10.3390/v3101815. PubMed PMID: 22069517; PubMed Central PMCID: PMC3205383.

7: Adnane J, Bizouarn FA, Qian Y, Hamilton AD, Sebti SM. p21(WAF1/CIP1) is upregulated by the geranylgeranyltransferase I inhibitor GGTI-298 through a transforming growth factor beta- and Sp1-responsive element: involvement of the small GTPase rhoA. Mol Cell Biol. 1998 Dec;18(12):6962-70. PubMed PMID: 9819384; PubMed Central PMCID: PMC109279.

8: Sun J, Qian Y, Chen Z, Marfurt J, Hamilton AD, Sebti SM. The geranylgeranyltransferase I inhibitor GGTI-298 induces hypophosphorylation of retinoblastoma and partner switching of cyclin-dependent kinase inhibitors. A potential mechanism for GGTI-298 antitumor activity. J Biol Chem. 1999 Mar 12;274(11):6930-4. PubMed PMID: 10066746.

9: Vogt A, Sun J, Qian Y, Hamilton AD, Sebti SM. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. J Biol Chem. 1997 Oct 24;272(43):27224-9. PubMed PMID: 9341167.

10: Duque G, Vidal C, Rivas D. Protein isoprenylation regulates osteogenic differentiation of mesenchymal stem cells: effect of alendronate, and farnesyl and geranylgeranyl transferase inhibitors. Br J Pharmacol. 2011 Mar;162(5):1109-18. doi: 10.1111/j.1476-5381.2010.01111.x. PubMed PMID: 21077849; PubMed Central PMCID: PMC3051383.

11: Lau CP, Huang L, Tsui SK, Ng PK, Leung PY, Kumta SM. Pamidronate, farnesyl transferase, and geranylgeranyl transferase-I inhibitors affects cell proliferation, apoptosis, and OPG/RANKL mRNA expression in stromal cells of giant cell tumor of bone. J Orthop Res. 2011 Mar;29(3):403-13. doi: 10.1002/jor.21249. PubMed PMID: 20886653.

12: Virtanen SS, Sandholm J, Yegutkin G, Kalervo Väänänen H, Härkönen PL. Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells. Cell Biol Int. 2010 Aug;34(8):815-26. doi: 10.1042/CBI20090288. PubMed PMID: 20446922.

13: Miquel K, Pradines A, Sun J, Qian Y, Hamilton AD, Sebti SM, Favre G. GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res. 1997 May 15;57(10):1846-50. PubMed PMID: 9157972.

14: Sarrabayrouse G, Pich C, Moriez R, Armand-Labit V, Rochaix P, Favre G, Tilkin-Mariamé AF. Melanoma cells treated with GGTI and IFN-gamma allow murine vaccination and enhance cytotoxic response against human melanoma cells. PLoS One. 2010 Feb 3;5(2):e9043. doi: 10.1371/journal.pone.0009043. PubMed PMID: 20140259; PubMed Central PMCID: PMC2815789.

15: Chen S, Fu L, Raja SM, Yue P, Khuri FR, Sun SY. Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis. Mol Cancer. 2010 Jan 29;9:23. doi: 10.1186/1476-4598-9-23. PubMed PMID: 20113484; PubMed Central PMCID: PMC2824632.

16: Kagami S, Owada T, Kanari H, Saito Y, Suto A, Ikeda K, Hirose K, Watanabe N, Iwamoto I, Nakajima H. Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3+ regulatory T cells. Int Immunol. 2009 Jun;21(6):679-89. doi: 10.1093/intimm/dxp037. PubMed PMID: 19380384.

17: Lee DH, Lee HR, Shin HK, Park SY, Hong KW, Kim EK, Bae SS, Lee WS, Rhim BY, Kim CD. Cilostazol enhances integrin-dependent homing of progenitor cells by activation of cAMP-dependent protein kinase in synergy with Epac1. J Neurosci Res. 2011 May;89(5):650-60. doi: 10.1002/jnr.22558. PubMed PMID: 21337364.

18: Ageberg M, Rydström K, Lindén O, Linderoth J, Jerkeman M, Drott K. Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines. Exp Cell Res. 2011 May 1;317(8):1179-91. doi: 10.1016/j.yexcr.2011.02.006. PubMed PMID: 21324313.

19: Abeles AM, Marjanovic N, Park J, Attur M, Chan ES, Al-Mussawir HE, Dave M, Fisher MC, Stuchin SA, Abramson SB, Pillinger MH. Protein isoprenylation regulates secretion of matrix metalloproteinase 1 from rheumatoid synovial fibroblasts: effects of statins and farnesyl and geranylgeranyl transferase inhibitors. Arthritis Rheum. 2007 Sep;56(9):2840-53. Erratum in: Arthritis Rheum. 2007 Oct;56(10):3510. Al-Mussawir, Hayfez [corrected to Al-Mussawir, Hayf E]. PubMed PMID: 17763406.

20: Alarcon VB, Marikawa Y. Statins inhibit blastocyst formation by preventing geranylgeranylation. Mol Hum Reprod. 2016 May;22(5):350-63. doi: 10.1093/molehr/gaw011. PubMed PMID: 26908642; PubMed Central PMCID: PMC4847613.