近日,，一隊(duì)來(lái)自新加坡國(guó)立大學(xué)（NUS）的生物科學(xué)系和機(jī)械生物學(xué)研究所的科學(xué)家團(tuán)隊(duì)已經(jīng)發(fā)現(xiàn)一種在研的潛在的藥物臨床前試驗(yàn)藥物的鉛化合物可以剝奪癌細(xì)胞的能量，阻止腫瘤細(xì)胞生長(zhǎng)成腫瘤,。這種藥物的先導(dǎo)化合物被命名為BPTES,。
這是第一次有研究能提供證據(jù)證實(shí)藥物的先導(dǎo)化合物能抑制腫瘤的形成。
在新研究發(fā)現(xiàn)的基礎(chǔ)上,，NUS研究團(tuán)隊(duì)對(duì)這一先導(dǎo)化合物進(jìn)行了衍生結(jié)構(gòu)修,，能更有效地殺死腎臟和乳腺癌細(xì)胞。相關(guān)研究論文發(fā)表在PNAS雜志上,。
通過 “饑餓”殺死癌細(xì)胞
癌癥生物學(xué)的經(jīng)典實(shí)驗(yàn)已經(jīng)證明癌細(xì)胞通過谷氨酰胺獲得能量,。雖然谷氨酰胺是促成這一系列生化反應(yīng)的第一個(gè)酶，但很少有人知道如何控制谷氨酰胺的活性,。
研究小組已經(jīng)成功地發(fā)現(xiàn)BPTES可以結(jié)合并抑制谷氨酰胺,，有效地阻斷腫瘤細(xì)胞的能量來(lái)源來(lái)餓死癌細(xì)胞，因此可有可能阻止腫瘤的生長(zhǎng),。
研究人員表示下一步的研究工作還需考慮優(yōu)化這一藥物,，提高其抑制腫瘤的效率并降低其副作用。（生物谷：Bioon.com）
doi:10.1073/pnas.1116573109
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Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism
K. Thangavelua, Catherine Qiurong Pana, Tobias Karlbergc, Ganapathy Balajid, Mahesh Uttamchandania,d,e, Valiyaveettil Sureshd, Herwig Schülerc, et al.
Besides thriving on altered glucose metabolism, cancer cells undergo glutaminolysis to meet their energy demands. As the first enzyme in catalyzing glutaminolysis, human kidney-type glutaminase isoform (KGA) is becoming an attractive target for small molecules such as BPTES [bis-2-(5 phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide], although the regulatory mechanism of KGA remains unknown. On the basis of crystal structures, we reveal that BPTES binds to an allosteric pocket at the dimer interface of KGA, triggering a dramatic conformational change of the key loop (Glu312-Pro329) near the catalytic site and rendering it inactive. The binding mode of BPTES on the hydrophobic pocket explains its specificity to KGA. Interestingly, KGA activity in cells is stimulated by EGF, and KGA associates with all three kinase components of the Raf-1/Mek2/Erk signaling module. However, the enhanced activity is abrogated by kinase-dead, dominant negative mutants of Raf-1 (Raf-1-K375M) and Mek2 (Mek2-K101A), protein phosphatase PP2A, and Mek-inhibitor U0126, indicative of phosphorylation-dependent regulation. Furthermore, treating cells that coexpressed Mek2-K101A and KGA with suboptimal level of BPTES leads to synergistic inhibition on cell proliferation. Consequently, mutating the crucial hydrophobic residues at this key loop abrogates KGA activity and cell proliferation, despite the binding of constitutive active Mek2-S222/226D. These studies therefore offer insights into (i) allosteric inhibition of KGA by BPTES, revealing the dynamic nature of KGA's active and inhibitory sites, and (ii) cross-talk and regulation of KGA activities by EGF-mediated Raf-Mek-Erk signaling. These findings will help in the design of better inhibitors and strategies for the treatment of cancers addicted with glutamine metabolism.
