GGTI-2418
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MedKoo CAT#: 205472

CAS#: 501010-06-6 (free acid)

Description: GGTI-2418, also known as PTX100, is a synthetic peptidomimetic inhibitor of geranylgeranyltransferase I (GGTase I) that appears to induce apoptosis by downregulating several pivotal oncogenic and tumor survival pathways. GGTase I catalyzes the lipid posttranslational modification which is required for the function of Rho GTPases (frequently found aberrantly activated in human cancer). GGTase I inhibitors block Rho function in cancer cells and induce a G1 phase cell cycle arrest by a mechanism involving induction of the CDK inhibitors p21waf and p27kip, CDK2 and CDK4 inhibition and hypophoshorylation of the tumor suppressor Rb. GGTase I inhibitors also induce apoptosis by a mechanism involving downregulation of the expression of survivin and suppression of the activation of PI3K/Akt.


Chemical Structure

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GGTI-2418
CAS# 501010-06-6 (free acid)

Theoretical Analysis

MedKoo Cat#: 205472
Name: GGTI-2418
CAS#: 501010-06-6 (free acid)
Chemical Formula: C23H31N5O4
Exact Mass: 441.2376
Molecular Weight: 441.532
Elemental Analysis: C, 62.57; H, 7.08; N, 15.86; O, 14.49

Price and Availability

Size Price Availability Quantity
200.0mg USD 1850.0 2 Weeks
500.0mg USD 2650.0 2 Weeks
1.0g USD 3950.0 2 Weeks
2.0g USD 6950.0 2 Weeks
Bulk inquiry

Related CAS #: 501010-05-5   501010-06-6 (free acid)   1044590-78-4 (sodium)  

Synonym: GGTI2418; GGTI-2418; GGTI 2418; PTX-100; PTX 100; PTX100

IUPAC/Chemical Name: (S)-2-((S)-2-benzyl-4-((4-methyl-1H-imidazol-5-yl)methyl)-3-oxopiperazine-1-carboxamido)-4-methylpentanoic acid.

InChi Key: COLCNDRDBCLVOC-ICSRJNTNSA-N

InChi Code: InChI=1S/C23H31N5O4/c1-15(2)11-18(22(30)31)26-23(32)28-10-9-27(13-19-16(3)24-14-25-19)21(29)20(28)12-17-7-5-4-6-8-17/h4-8,14-15,18,20H,9-13H2,1-3H3,(H,24,25)(H,26,32)(H,30,31)/t18-,20-/m0/s1

SMILES Code: CC(C)C[C@H](NC(N1[C@@H](CC2=CC=CC=C2)C(N(CC3=C(C)N=CN3)CC1)=O)=O)C(O)=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, 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

Product Data:

Biological target: GGTI-2418 is a highly potent, competitive, and selective geranylgeranyltransferase I (GGTase I) inhibitor. GGTI-2418 inhibits GGTase I and FTase activities with IC50s of 9.5 nM and 53 μM, respectively.
In vitro activity: In vitro, GGTI-2418 inhibited GGTase I and FTase activities with 50% inhibitory concentrations (IC50s) of 9.5 ± 2.0 nM and 53 ± 11 μM, respectively, a 5,600-fold selectivity toward inhibition of GGTase I versus FTase. GGTI-2418 demonstrated competitive inhibition of GGTase I against the H-Ras-CVLL protein with a Ki value of 4.4 ± 1.6 nM (Fig. 1C). Reference: Mol Cell Biol. 2009 Apr;29(8):2254-63. https://pubmed.ncbi.nlm.nih.gov/19204084/
In vivo activity: In contrast, treatment with GGTI-2418 at 100 mg/kg/day not only halted tumor growth, but also actually induced massive tumor regression within a few days. Figures 5B and C show a representative example of a tumor that decreased by 76% following GGTI-2418 treatment. The degree of regression was independent of the size of the tumor before initiation of treatment; in seven mice with a total of 17 tumors, treatment with 100 mg/kg GGTI-2418 resulted in tumor regression between 34 and 100%, with an average of 60% ± 4% (standard error of the mean) (see Table S1 in the supplemental material). Reference: Mol Cell Biol. 2009 Apr;29(8):2254-63. https://pubmed.ncbi.nlm.nih.gov/19204084/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 125.0 283.11

Preparing Stock Solutions

The following data is based on the product molecular weight 441.532 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. Kazi A, Carie A, Blaskovich MA, Bucher C, Thai V, Moulder S, Peng H, Carrico D, Pusateri E, Pledger WJ, Berndt N, Hamilton A, Sebti SM. Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol Cell Biol. 2009 Apr;29(8):2254-63. doi: 10.1128/MCB.01029-08. Epub 2009 Feb 9. PMID: 19204084; PMCID: PMC2663293.
In vitro protocol: 1. Kazi A, Carie A, Blaskovich MA, Bucher C, Thai V, Moulder S, Peng H, Carrico D, Pusateri E, Pledger WJ, Berndt N, Hamilton A, Sebti SM. Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol Cell Biol. 2009 Apr;29(8):2254-63. doi: 10.1128/MCB.01029-08. Epub 2009 Feb 9. PMID: 19204084; PMCID: PMC2663293.
In vivo protocol: 1. Kazi A, Carie A, Blaskovich MA, Bucher C, Thai V, Moulder S, Peng H, Carrico D, Pusateri E, Pledger WJ, Berndt N, Hamilton A, Sebti SM. Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol Cell Biol. 2009 Apr;29(8):2254-63. doi: 10.1128/MCB.01029-08. Epub 2009 Feb 9. PMID: 19204084; PMCID: PMC2663293.

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1. Kazi A, Carie A, Blaskovich MA, Bucher C, Thai V, Moulder S, Peng H, Carrico D, Pusateri E, Pledger WJ, Berndt N, Hamilton A, Sebti SM. Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol Cell Biol. 2009 Apr;29(8):2254-63. Epub 2009 Feb 9. PubMed PMID: 19204084; PubMed Central PMCID: PMC2663293.

GGTI-2418

200.0mg / USD 1850.0


Additional Information

GGTI-2418 is a potent and selective peptidomimetic inhibitor of geranylgeranyltransferase I (GGTI).
 
GGTI-2418 , and its methyl ester GGTI-2417, which increases the levels of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) and induces breast tumor regression in vivo. Experiments with p27(Kip1) small interfering RNA in breast cancer cells and p27(Kip1) null murine embryonic fibroblasts demonstrate that the ability of GGTI-2417 to induce cell death requires p27(Kip1). GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27(Kip1) at Thr187 and accumulates p27(Kip1) in the nucleus. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. Furthermore, in ErbB2 transgenic mice, GGTI-2418 increases p27(Kip1) and induces significant regression of breast tumors. We conclude that GGTIs' antitumor activity is, at least in part, due to inhibiting Cdk2-dependent p27(Kip1) phosphorylation at Thr187 and accumulating nuclear p27(Kip1). Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear p27(Kip1) [source: Mol Cell Biol. 2009 Apr;29(8):2254-63. Epub 2009 Feb 9.]