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Inhibitors of protein prenyltransferases

A protein and alkyl technology, applied in the fields of organic chemistry, antitumor drugs, drug combination, etc., can solve the problems of different yields, great differences in reaction conditions, and hindering the adjustment of combinatorial library synthesis methods.

Inactive Publication Date: 2009-05-13
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to widely varying reaction conditions, yields vary widely from reaction to reaction, hampering adaptation of methods for combinatorial library synthesis in solid phase

Method used

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  • Inhibitors of protein prenyltransferases
  • Inhibitors of protein prenyltransferases
  • Inhibitors of protein prenyltransferases

Examples

Experimental program
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Effect test

Embodiment 1

[0246] We report the first example of phosphine catalysis of polymer-bonded allenoate esters and a combinatorial library approach to the development of highly potent inhibitors of the type I protein geranylgeranyltransferase (GGTase-I).

[0247] A panel of 138 heterocycles were screened for their ability to inhibit the activity of human GGTase-I in geranylating K-Ras4B or RhoA geranyl. The purified GGTase-I and its substrate protein K-Ras4B or RhoA, [ 3 H]GGPP, and 138 compounds were incubated together. After 30 minutes, the degree of incorporation of deuterated geranylgeranyl was measured using a scintillation counter.

[0248] A variety of compounds have been identified as GGTIs, including those numbered 1 and 2 below:

[0249]

[0250] The discovery of a promising GGTI lead compound and its modest activity warrants the development of efficient and rapid synthesis and evaluation of similar structures in search of better inhibitors; we conceived a method using SynPhase ...

Embodiment 2

[0271] Such as Figure 20 As shown in A-20C, compounds P3-E5 and P5-H6 specifically inhibit GGTase I. The figure illustrates the effect of P3-E5 and P5-H6 on the enzymatic activity of GGTase-I (A), FTase (B), GGTase-II (C). Different concentrations of the two compounds were added to each enzyme reaction. K-Ras4B, FT enzyme (JENA Bioscience, SanDiego, CA) and [ 3 H] Farnesyl pyrophosphate for FT enzyme (protein farnesyl transferase) assay. Incubate at 37°C for 30 minutes.

[0272] Using RhoA as substrate protein, GGTase-I (JENA Bioscience) and [ 3 H] Geranylgeranyl pyrophosphate for GGTase-I assay. Incubate at 37°C for 30 minutes. Using YPT1, GGTase-II (Calbiochem, San Diego, CA) and REP1 (Calbiochem) as substrate proteins and [ 3 H] Geranylgeranyl pyrophosphate for GGTase-II (or RabGGTase) assay. Incubate at 37°C for 30 minutes. Figure 20 D-20F shows the three-dimensional structures of GGTase I (D), FTase (E) and GGTase II (F), which can be obtained from X-ray diffra...

Embodiment 3

[0274] Such as Figure 21 As shown in A-21D, P3-E5 and P5-H6 compete with substrate proteins but not with GGPP. Figure 21 The panel in shows the double reciprocal plot of the inhibition of GGTase-I by P3-E5 (left) and P5-H6 (right) from the substrate rate curves. The upper graph shows the use of a fixed RhoA protein concentration as well as varying GGPP concentrations. The graph below shows the use of a fixed GGPP concentration as well as varying RhoA protein concentrations. Graphs are plotted using the following symbols: Y-axis: 1 / v, fmol / min. X-axis: 1 / s, mM.

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Abstract

The present invention is directed to novel compounds. These compounds can be useful in inhibiting the activity of GGTase I. The compounds can also be used as anti-cancer therapeutics including as part of methods for treating cancer, in assays, and in kits.

Description

[0001] Embodiments of this invention were made with government support under grant number CA32737 from the NIH. The government may have certain rights in this invention. Background technique [0002] Certain protein prenyltransferases are involved in the cancer process. Two such prenyltransferases—the protein farnesyltransferase (FTase) and the protein geranylgeranyltransferase (GGTase I)—are considered to be structurally similar enzymes. See Protein Lipidation (2001) The Enzymes vol. 21. (eds. Tamanoi, F. and Sigman D.S.) Academic Press. FT enzymes consist of two subunits α and β. Its structure consists only of alpha helices, the alpha subunits winding around the beta subunits forming a beta-beta barrel structure. GGTase I is also a heterodimer containing the alpha subunit that FTase also contains. Furthermore, the β subunit of GGTase I is very similar to the β subunit of FTase. [0003] FT enzymes catalyze the C15 farnesyl conversion of farnesyl pyrophosphate (intermedi...

Claims

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Application Information

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IPC IPC(8): A61K31/40C07D207/18
CPCC07D211/96C07D207/48A61P35/00A61P35/02A61P43/00
Inventor 玉野井冬彦权五铉渡边胜汉娜·斐济
Owner RGT UNIV OF CALIFORNIA
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