Ras
RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. In normal mammalian cells, RAF kinases (ARAF, BRAF, and CRAF) are major RAS effectors. Ras1 activates a MAP kinase cascade, although in this organism, the kinase that Ras1 activates directly, Byr2, does not resemble RAF. On the other hand, RAS proteins (RAS1p and RAS2p) activate adenylate cyclase and regulate production of cyclic AMP (cAMP) in response to intracellular glucose. Mutations in RAS regulators, such as neurofibromin and SPRED1, also make significant contributions to cancer. Abnormal RAS activity may also play a significant role in autism and other neurological disorders. RAS proteins are binary molecular switches that cycle between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound states. This switch mechanism has been highly conserved among GDP/GTP binding proteins as diverse as bacterial elongation factors, heterotrimeric G-proteins, and a myriad of small GTPases with diverse biological functions.
GEFs and GAPs are large, multi-domain proteins capable of an astonishing variety of interactions with other proteins, lipids, and regulatory molecules that control levels of active and inactive RAS. Dependence of RAS and other GTPases on GEFs and GAPs to switch them on and off allows both processes to be highly regulated and responsive to multiple signal inputs. RAS proteins activate effectors by recruitment to the plasma membrane. Indeed, for RAF kinase, translocation appears to be sufficient to initiate the complicated activation process. Recruitment of RalGDS to RAS in the plasma membrane leads to activation of RalA and RalB. Recruitment of PI 3-kinase γ (PI3Kγ) to the plasma membrane through a myristoylation signal rescues a mutant that does not bind RAS, suggesting membrane recruitment is a critical step in the activation process. RAS proteins play a causal role in human cancer: this has been recognized for many years and has inspired multiple attempts to find RAS inhibitors.
References
1.Simanshu DK,et al. Cell. 2017;170(1):17–33.
GEFs and GAPs are large, multi-domain proteins capable of an astonishing variety of interactions with other proteins, lipids, and regulatory molecules that control levels of active and inactive RAS. Dependence of RAS and other GTPases on GEFs and GAPs to switch them on and off allows both processes to be highly regulated and responsive to multiple signal inputs. RAS proteins activate effectors by recruitment to the plasma membrane. Indeed, for RAF kinase, translocation appears to be sufficient to initiate the complicated activation process. Recruitment of RalGDS to RAS in the plasma membrane leads to activation of RalA and RalB. Recruitment of PI 3-kinase γ (PI3Kγ) to the plasma membrane through a myristoylation signal rescues a mutant that does not bind RAS, suggesting membrane recruitment is a critical step in the activation process. RAS proteins play a causal role in human cancer: this has been recognized for many years and has inspired multiple attempts to find RAS inhibitors.
References
1.Simanshu DK,et al. Cell. 2017;170(1):17–33.
MAPK/ERK Signaling
Ras
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ADT-007
产品货号 : M37557
cas no: 1945941-09-2
ADT-007 is an orally active and selective pan-RAS inhibitor with potent anticancer activity.ADT-007 blocks GTP activation of RAS and MAPK/AKT signaling by binding to anucleotide RAS.ADT-007 is used in the study of gastrointestinal cancers. -
RMC-6236
产品货号 : M36608
cas no: 2765081-21-6
RAS-IN-2 (Compound A122) 是一种有效的 RAS(ON)MULTI 抑制剂,可用于癌症的研究。 -
(R)-BI-2852
产品货号 : M36442
cas no: 2375482-49-6
(R)-BI-2852 是 BI-2852 (HY-126247) 的非活性异构体,可作为实验中的对照化合物。BI-2852 是基于活性分子结构设计的 switch SI/II 口袋的 KRAS 抑制剂,其通过基于结构的活性分子设计具有纳摩尔亲和力。BI-2852 在机理上不同于共价 KRASG12C 抑制剂 (结合 switch II),与活性 KRASG12D 结合强度是与 KRAS wt 的 10 倍 (740 nM vs 7.5 μM)。BI-2852 阻断 GEF,GAP 和效应子与 KRAS 的相互作用,导致下游信号传导的抑制和 KRAS 突变细胞中的抗增殖作用。 -
J-104871
产品货号 : M33992
cas no: 191088-19-4
J-104871 (UNII-6137X5QNJF) is a novel farnesyltransferase (FTase) inhibitor that competitively blocks Ras farnesylation in vivo, inhibits Ras processing in activated H-ras-transformed NIH3T3 cells, and suppresses tumor growth in nude mice transplanted with activated H-ras-transformed NIH3T3 cells. -
Rac1 Inhibitor W56
产品货号 : M30824
cas no: 1095179-01-3
Peptide comprising residues 45-60 of the guanine nucleotide exchange factor (GEF) recognition/activation site of Rac1; selectively inhibits Rac1 interaction with Rac1-specific GEFs TrioN, GEF-H1 and Tiam1.