2008-541 SMALL MOLECULE INHIBITORS OF GERANYLGERANYLTRANSFERASE-I AND II

Novel Non-Peptidomimetic Prenyltransferase Inhibitors

SUMMARY

UCLA Researchers in the Department of Chemistry & Biochemistry and School of Medicine have synthesized a series of small molecule therapeutics against GGTase-I and GGTase-II, both of which are critical oncology drug targets.

BACKGROUND

The Ras protein is typically abnormally active in cancer cells. Farnesyltransferase inhibitors (FTIs) are a class of cancer drugs that inhibits farnesylation of Ras proteins, thereby preventing the proper functioning of Ras. However, a key escape pathway for these oncogenic cells treated with FTIs is geranylgeranylation, a form of prenylation that serves as a functional substitute for farnesylation. This process can be catalyzed by either geranylgeranyltransferase (GGTase-I) or Rab geranylgeranyltransferase (RabGGTase or GGTase-II). In vivo studies on GGTase-I knockout mice have shown that inhibiting GGTase-I leads to tumor growth inhibition and induces apoptosis in cell lines. Small molecule antagonists of GGTase-I and GGTase-II are therefore promising candidates for fully blocking activation of Ras.

INNOVATION

A novel series of small molecule oncology therapeutics have been developed by UCLA Professors Ohyun Kwon and Fuyu Tamanoi. Structure-activity relationship (SAR) studies have elucidated important structural features of these compounds that can be modified for specific targeting of either GGTase-I, GGTase-II, or both.

The inventors have demonstrated the ability of the lead compounds to inhibit GGTAse-I geranylgeranylation of RhoA and KRas4B with in vivo studies of pancreatic and lung cancer models. In vivo studies on SCID mice with PANC-1 xenografts show a three-fold reduction in tumor volume at half the maximum-tolerated dose of one of the lead compounds with no effect on body weight. They show activity in a number of human cell lines including PANC-1 and MiaPaCa2. The inventors have also demonstrated that one of the lead compounds inhibits proliferation of NSCLC cell lines H358, H23 and H1507 by inhibiting geranylgeranylation, membrane association of RhoA and causing G1 accumulation associated with decreased cyclin D1/2. Control studies with an RhoA-F mutant suggests that the inhibition of proliferation occurs through the inhibition of RhoA. The compounds have been shown to be substrate-specific inhibitors and do not inhibit other prenyltransferases.

APPLICATIONS

• Treatment of cancer
• Pancreatic
• Non-small cell lung
• Breast

ADVANTAGES

• Specificity
• Activity in several cell lines
• Molecular target is known
• First non-peptidomimetic leads against these targets

STATE OF DEVELOPMENT

The efficacy of the lead compounds have been demonstrated in in vivo studies, and SARs have been established. The molecular target is known and a crystal structure has been obtained. Further dose-response studies will be conducted.

RELATED MATERIALS

• S. Castellano, H. D. G. Fiji, S. S. Kinderman, M. Watanabe, P. de Leon, F. Tamanoi, and O. Kwon. Small-Molecule Inhibitors of Protein Geranylgeranyltransferase Type I, J. Am. Chem. Soc., 2007.
• M. Watanabe, H. D. G. Fiji, L. Guo, L. Chan, S. S. Kinderman, D. Slamon, O. Kwon, and F. Tamanoi. Inhibitors of Protein Geranylgeranyltransferase I and Rab Geranylgeranyltransferase Identified from a Library of Allenoate-derived Compounds, Journal of Biological Chemistry, 2008.
• J. Lu, L. Chan, H. D. G. Fiji, R. Dahl, O. Kwon, and F. Tamanoi. In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I, Molecular Cancer Therapeutics, 2009.
• L. N. Chan, H. D. G. Fiji, M. Watanabe, O. Kwon, and F. Tamanoi, F. Identification and Characterization of Mechanism of Action of P61-E7, a Novel Phosphine Catalysis-Based Inhibitor of Geranylgeranyltransferase-I, PLoS ONE, 2011.
• D. B. Zimonjic, L. N. Chan, V. Tripathi, J. Lu, O. Kwon, N. C. Popescu, D. R. Lowy, and F. Tamanoi. In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells, BMC Cancer, 2013.

J. Lu, K. Yoshimura, K. Goto, C. Lee, K. Hamura, O. Kwon, and F. Tamanoi. Nanoformulation of Geranylgeranyltransferase-I Inhibitors for Cancer Therapy: Liposomal Encapsulation and pH-Dependent Delivery to Cancer Cells, PLoS ONE, 2015.