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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.
MedKoo Cat#: 205472
CAS#: 501010-06-6 (free acid)
Chemical Formula: C23H31N5O4
Exact Mass: 441.2376
Molecular Weight: 441.52
Elemental Analysis: C, 62.57; H, 7.08; N, 15.86; O, 14.49
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
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.]
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.