ty in cancer cells"， Proc.Natl.Acad.Sci.U.S.A. (2005) 102:4336-4341)或棕榈酰基转移酶。FTase抑制剂作为 kRAS活性的调节物已经进行了最广泛研抑制剂(Sebti等，"Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies'，，0ncogene(2000)9:6584-6593 ; Cox 等，"Farnesyl transferase inhibitors: promises and realities'，， Curr.Opin.Pharmacol. (2002)2:388-393)分为两类:CAAX肽模拟物，包括FTI-276(Sun等， "Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Rasprenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts"，Oncogene (1998)16:1467-1473)、FTI-277(Lerner等，"Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes"，J·Biol·Chem.(1995)270:26802-26806)、L_744832(Song等，"K-Ras-independent effects of the farnesyl transferase inhibitor L_744,832 on cyclin Bl/Cdc2 kinase activity,G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells'，， Neoplasia(2000)2:261-272)、B956(Nagasu等，"Inhibition of human tumor xenograft growth by treatment with the farnesyltransferase inhibitor B956"，Cancer Res· (1995)55,5310_5314)和FTI_2153(Crespo等，"The farnesyltransferase inhibitor， FTI-2153,blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells'，， J.Biol.Chem. (2001)276:16161-16167);以及非肽模拟物，其包括替吡法尼（tipifamib) (Beaupre等·"R115777induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways ·"，Mol · Cancer Ther · (2004)3 :179-186)、洛那法尼 (lonafarnib)(Wang等，"The farnesyl protein transferase inhibitor lonafarnib (SCH66336) is an inhibitor of multidrug resistance proteins 1 and 2'，， Chemotherapy(2003)49:303-308)和BMS-214662(Rose等·"Preel inical antitumor activity of BMS-214662.；a highly apoptotic and novel farnesyltransferase inhibitor"，Cancer Res. (2001 )61,7507-7517)。最近的许多出版物描述了其临床前效力 (Haluska等，"Farnesyltransferase inhibitors as anticancer agents'，，Eur.J.Cancer (2002)38,1685_1700;Sebti，"Blocked pathways:FTIs shut down oncogene signals''， 01^〇1(^18〖(2003)8(增刊3):30-38)。但是，这些试剂似乎均未朝向批准市售前进。
[0010] 用于kRAS抑制的上游革E标包括酪氨酸激酶（Sawyers.，"Rational therapeutic intervention in cancer:kinases as drug targets^,Curr.Opin.Genet.Dev.(2002)12: 111-115)、GRB2/GEF相互作用（Quill iam 等，"Membrane-targe ting potentiates guanine nucleotide exchange factor CDC25 and S0S1 activation of RAS transforming activity"，Proc·Nat 1·Acad.Sci.U.S.A.(1994);91:8512-8516)和GEF(Shields等， "Understanding RAS: "it ain't over'til it's over? ,Trends Cell Biol. (2000)10； 147-154)。
[0011] RAS蛋白在无活性⑶P结合形式和活性GTP结合形式之间循环。该激活状态由GEF和 GAP调节（图3)(Reuther等，"The RAS branch of small GTPases:RAS family members don't fall far from the tree?，,Curr.Opin.Cell Biol · (2000) 12:157-165;Takai等， "Smal1 GTP-binding proteins.Physiol.Rev.(2001)81:153-208;Cullen等· "Integration of calcium and RAS signaling"，Nat.Rev.Mol.Cell Biol.(2002)；3: 339-348;Heldin，"Dimerization of cell surface receptors in signal transduction"，Ce11 ( 1995)80:213-223;Lemmon等，"Regulation of signal transduction and signal diversity by receptor oligomerization'，，Trends Biochem.Sci.(1994)19:459-463;Weiss等，"Novel mechanisms of RTK signal generation"，Curr · Opin .Genet .Dev. (1997)7:80-86) D 当生长因子与酪氨酸激酶受体结合 时，其形成活性同二聚体，后者经历自磷酸化。这导致接头蛋白SHC与生长因子受体结合2 (growth factor receptor bound 2，GRB2)结合DGRB2然后与GEF通过其SH3结构域缔和。 GEF将结合的GDP交换成GTP，从而激活RAS蛋白并且启动信号传导级联。为了终止信号传导， GAP刺激RAS蛋白固有的GTP酶活性，引起GTP水解成⑶P，导致RAS蛋白失活。
[0012]虽然众所周知难以调节蛋白质-蛋白质相互作用如RAS/GEF，但是已经鉴定了多种 RAS-GEF。大部分研究工作集中于kRAS与特定GEF--son of sevenless(SOS)的相互作用。 与kRAS/SOS接触表面相邻的口袋能够与小分子结合(Maurer等.，"Small-moleculeligands bind to a distinct pocket in RAS and inhibit SOS-mediated nucleotide exchange activity"，Proc.Natl. Acad. Sci.U.S. A. (2012)109:5299-5304)，并且基于 NMR 的片段筛选 最近鉴定了同与kRAS/SOS接触表面相邻的口袋结合并且随后干扰kRAS/SOS相互作用的小 分子。但是，未报道来自该方法的药物候选物。
[0013] kRAS可以与许多下游效应蛋白相互作用，以改变细胞存活和增殖（图4) (Schlessinger，"Cell signaling by receptor tyrosine kinases'，，Cell(2000)103: 211-225;Repasky等，"Renewing the conspiracy theory debate : does Raf function alone to mediate RAS oncogenesis?"，Trends Cell Biol(2004)14:639_647)Di要包括 RAF蛋白激酶、磷脂酰肌醇3-激酶(PI3K)、RAS相关蛋白Ral的鸟苷酸交换因子(RalGDS)和磷 脂酶Ce(PLC ehRAF启动丝裂原活化蛋白（MAP)激酶级联，其激活细胞外信号调节激酶 (ERKh这种活性激酶具有多个靶标，包括转录因子ELK1，其调节细胞周期进展基因的表达 (Leevers等，"Requirement for RAS in Raf activation is overcome by targeting Raf to the plasma membrane"，Nature(1994)369:411-414;Marais等，"RAS recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation"，EMB0 J.(1995)14:3136_3145;Finney等，"RAS-Raf complexes:analyses of complexes formed in vivo"，Methods Enzymol·(1995)255，310-323;Johnson等，"Identification of key residues in the A-Raf kinase important for phosphoinositide lipid binding specificity"，Biochemistry(2005)44:3432_3440;Ghosh等，"Functional analysis of a phosphatidic acid binding domain in human Raf-1 kinase:mutations in the phosphatidate binding domain lead to tail and trunk abnormalities in developing zebrafish embryos"，J.Biol .Chem. (2003)278:45690-4569