Surface binding inhibitors of the SCF-KIT protein-protein interaction.
Surface binding inhibitors of the SCF-KIT protein-protein interaction.
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DOI：
10.1002/cbic.200900079
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发表时间：
2009-08-17
期刊：
影响因子：
3.2
通讯作者：
Hamilton, Andrew D.
中科院分区：
文献类型：
--
作者：
Margulies, David;Opatowsky, Yarden;Fletcher, Steven;Saraogi, Ishu;Tsou, Lun K.;Saha, Sourav;Lax, Irit;Schlessinger, Joseph;Hamilton, Andrew D.
KIT是一种受体酪氨酸激酶(RTK)，其与其配体干细胞因子(SCF)的相互作用对多种细胞的生长和分化是必不可少的。[1]SCF结合促进KIT二聚化、[2]转磷酸化和激活下游细胞信号通路，对细胞的增殖、分化和生存至关重要。已在胃肠道间质瘤(GIST)等人类癌症中发现了KIT中的获得性功能突变。[3，4]还证明了SCF和/或KIT异常表达所介导的自分泌或旁分泌机制也可能导致肿瘤发生。[5-7]由于大多数GIST病例是由致癌的KIT突变引起的，导致酪氨酸激酶活性增强，KIT酪氨酸激酶[8]活性的抑制剂，如格列卫®(甲磺酸伊马替尼)和Sutent®(孙尼替尼)，另一种抑制RTK活性的方法是阻断配体与受体的结合。[9]虽然这可以通过使用单抗有效地实现，但开发更不容易酶降解、可以口服并且更易于修饰的非肽蛋白结合物是非常必要的。然而，实现这种抑制物在分子识别和药物发现中是一个具有挑战性的目标，因为两种蛋白质之间的相互作用通常涉及复杂的、大的和浅的界面，这些界面缺乏凹槽和口袋来容纳传统的小分子抑制剂。锁定关键的相互作用部位，即所谓的“热点”，对蛋白质-蛋白质复合体的稳定性有重要贡献，是一种可以用来破坏配体-受体接触的方法[13]。用合成试剂寻找和定位这些位点的系统方法仍有待开发。
KIT is a receptor tyrosine kinase (RTK), the interaction of which with its ligand, stem cell factor (SCF), is essential for growth and differentiation of various cells.[1] SCF binding promotes KIT dimerization,[2] transphosphorylation, and activation of downstream cell signaling pathways essential for cell proliferation, differentiation, and survival. Gain-offunction mutations in KIT have been identified in human cancers such as gastrointestinal stromal tumors (GIST).[3, 4] It was also demonstrated that autocrine or paracrine mechanisms mediated by aberrant expression of SCF and/or KIT might also lead to oncogenesis.[5–7] Because most cases of GIST are driven by oncogenic KIT mutations resulting in enhanced tyrosine kinase activity, inhibitors of the tyrosine kinase [8] activity of KIT, such as Gleevec®(imatinib mesylate) and Sutent®(sunitinib), have been successfully applied for the treatment of GIST patients.Another way to inhibit the activity of RTKs such as KIT is to block the binding of the ligand to the receptor.[9] Although this can effectively be achieved by using monoclonal antibodies,[10] the development of nonpeptidic protein binders that might be less susceptible to enzymatic degradation, could be taken orally, and would be more amenable to modification is highly desired.[11, 12] Realizing such inhibitors, however, is a challenging goal in molecular recognition and drug discovery because the interactions between two proteins normally involve complex, large, and shallow interfaces that lack grooves and pockets to accommodate traditional small-molecule inhibitors. Targeting key interaction sites, so called “hot-spots”, which contribute significantly to the stability of protein–protein complexes, is one approach [13] that could be taken to disrupt ligand–receptor contacts. A systematic method for finding and targeting these sites with synthetic agents remains to be developed.
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影响因子：
5.2
作者：
Jain, RK;Hamilton, AD
通讯作者：
Hamilton, AD
DOI：
10.1073/pnas.082675899
发表时间：
2002-04-16
影响因子：
11.1
作者：
Park, HS;Lin, Q;Hamilton, AD
通讯作者：
Hamilton, AD
影响因子：
16.6
作者：
Rodriguez, Johanna M.;Hamilton, Andrew D.
通讯作者：
Hamilton, Andrew D.
影响因子：
18.3
作者：
Horne, W. Seth;Gellman, Samuel H.
通讯作者：
Gellman, Samuel H.
影响因子：
46.9
作者：
Blaskovich, MA;Lin, Q;Sebti, SM
通讯作者：
Sebti, SM