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Development of multivalent inhibitor...

Gorczynski, Michael Jason.

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Development of multivalent inhibitors for two protein-protein interactions associated with human leukemia.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Development of multivalent inhibitors for two protein-protein interactions associated with human leukemia./
作者:	Gorczynski, Michael Jason.
面頁冊數:	259 p.
附註:	Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4815.
Contained By:	Dissertation Abstracts International66-09B.
標題:	Chemistry, Organic. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3189288
ISBN:	0542319357

Development of multivalent inhibitors for two protein-protein interactions associated with human leukemia.
Gorczynski, Michael Jason.

Development of multivalent inhibitors for two protein-protein interactions associated with human leukemia. - 259 p.

Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4815.

Thesis (Ph.D.)--University of Virginia, 2005.

The inhibition of protein-protein interactions is an interesting and relatively new strategy for the treatment of diseases such as leukemia. Several protein-protein interactions associated with human leukemia arise from chromosome alterations. The inv(16) produces CBFbeta-SMMHC, a dimeric protein that is involved in the development of acute myeloid leukemia (AML) when it forms a heterodimer with AML1. Similarly, a form of chronic myeloid leukemia (CML) develops as a result of the t(9:22), which produces another oligomeric (tetramer) protein, BCR-ABL. Unfortunately, current treatments for these diseases are toxic and several are becoming ineffective due to cellular resistance mechanisms. Therefore, multivalent inhibitors were developed in order to selectively inhibit these protein-protein interactions (CBFbeta-SMMHC and BCR-ABL) while minimally inhibiting the wildtype proteins (CBFbeta and ABL).

ISBN: 0542319357Subjects--Topical Terms:

516206
Chemistry, Organic.

Development of multivalent inhibitors for two protein-protein interactions associated with human leukemia.
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245 1 0 $a Development of multivalent inhibitors for two protein-protein interactions associated with human leukemia.
300 $a 259 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-09, Section: B, page: 4815.
500 $a Adviser: Milton L. Brown.
502 $a Thesis (Ph.D.)--University of Virginia, 2005.
520 $a The inhibition of protein-protein interactions is an interesting and relatively new strategy for the treatment of diseases such as leukemia. Several protein-protein interactions associated with human leukemia arise from chromosome alterations. The inv(16) produces CBFbeta-SMMHC, a dimeric protein that is involved in the development of acute myeloid leukemia (AML) when it forms a heterodimer with AML1. Similarly, a form of chronic myeloid leukemia (CML) develops as a result of the t(9:22), which produces another oligomeric (tetramer) protein, BCR-ABL. Unfortunately, current treatments for these diseases are toxic and several are becoming ineffective due to cellular resistance mechanisms. Therefore, multivalent inhibitors were developed in order to selectively inhibit these protein-protein interactions (CBFbeta-SMMHC and BCR-ABL) while minimally inhibiting the wildtype proteins (CBFbeta and ABL).
520 $a In order to begin these studies, LUDI was used to identify compounds that interacted with CBFbeta and these "hits" were screened using 15N-1H HSQC NMR. Several compounds, namely 2-aminothiazoles, perturbed amino acids of CBFbeta suggesting that these compounds bind to CBFbeta. Therefore, a library of 2-aminothiazoles was synthesized using traditional medicinal chemistry techniques. All of the thiazoles were screened by 15N-1H HSQC NMR, to determine if the compounds bind to CBFbeta and also by FRET, in order to determine how well the compounds bind to CBFbeta (IC50) and how effective the compounds are at dissociating the CBFbeta-AML1 complex (Delta). A number of dimers (thiazole tethered to same thiazole) have been synthesized and were more active than the monomers in vitro.
520 $a CML is commonly treated with the tyrosine kinase inhibitor, Gleevec, which is a highly selective ATP mimic. Unfortunately, more and more patients are becoming resistant to Gleevec treatment because of the formation of additional mutations in the ABL kinase. In an attempt to bypass these resistance mechanisms, Gleevec has been modified by tethering one Gleevec to another Gleevec, to form a multivalent inhibitor, in order to impart higher selectivity and potency for BCR-ABL.
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