KRAS-targeted Drugs R&D Service

1

تصويت

RAS is one of the most frequently mutated oncogenes in human cancer. KRAS is the isoform most frequently mutated, which constitutes about 85% of RAS mutations. As the most frequently mutated RAS isoform, https://www.medicilon.com/platform/kras/ is intensively studied in the past years.

In the formulation of KRAS integrated research plan, Medicilon has in-depth communication with customers. The backbone of scientific research has combined the characteristics of each case with years of practical experience and technical accumulation, and carefully submitted high-quality experimental plans and results to customers. Medicilon provides KRAS-targeted drug discovery, CMC research (API + formulation), pharmacodynamics research, PK study, safety evaluation and other services. Introduction of KRAS RAS is a family of GTPase proto-oncogenes, comprising three closely related RAS isoforms: HRAS, KRAS and NRAS. From all of the RAS isoforms, KRAS is most frequently mutated, followed by NRAS and then HRAS. KRAS mutations are particularly frequent in the pancreatic, lung and colorectal cancers. In cancer, the most frequently mutated residues are G12, G13, and Q61. KRAS protein exists as two splice variants, KRAS4A and KRAS4B, in which KRAS4B is the dominant form in human cells. KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) gene is a proto-oncogene that encodes a GTP/GDP-binding protein that belongs to the GTPase RAS family. The KRAS protein acts as molecular switchs that cycle between a GDP-bound inactive state and a GTP-bound active state. KRAS protein switches between an inactive to an active form via binding to GTP and GDP, respectively. Although the KRAS protein harbors both intrinsic nucleotide exchange and GTP hydrolysis, its cellular signaling state arises from activation by guanine exchange factors (GEFs), such as son of sevenless (SOS) and Ras guanyl nucleotide-releasing protein, which catalyze GTP loading and deactivation by GTPase activating proteins (GAPs), such as p120GAP and neurofibromin (NF1), which stimulate GTP hydrolysis. Structure of KRAS KRAS protein contains four domains. The first domain at the N-terminus is identical in the three RAS forms, and the second domain exhibits relatively lower sequence identity. Both regions are important for the signaling function of the KRAS protein and jointly form the G-domain. KRAS protein has a molecular weight of 21 kDa, and is made up of six beta-strands (forming the protein core) and five alpha-helices, which form two major domains: the G-domain and the C-terminal. The G domain of KRAS, comprised of residues 1-166, includes the GTP-binding pocket, a region within which is essential for the interactions between the putative downstream effectors and GTPase-activating proteins (GAPs). The G domain is highly conserved and contains switch I and switch II loops, which are responsible for GDP-GTP exchange. The C-terminal, a hypervariable region including the CAAX (C= cysteine, A = any aliphatic amino acid, X = any amino acid) motif, guides posttranslational modifications and determines plasma membrane anchoring. This region plays an important role in the regulation of the biological activity of RAS protein. Signal Pathway of KRAS Signaling KRAS is one of front-line sensors that initiate the activation of an array of signaling molecules, allowing the transmission of transducing signals from the cell surface to the nucleus, and affecting a range of essential cellular processes such as cell differentiation, growth, chemotaxis and apoptosis. In addition to the aforementioned GTP/GDP binding, the activation of KRAS signaling is now known as a multi-step process that requires proper KRAS post-translation, plasma membrane-localization and interaction with effector proteins. The signal transduction of the KRAS protein does not exclusively occur at the plasma membrane. Activation of downstream signaling pathways by KRAS can also be triggered by signals from subcellular compartments, such as the endoplasmatic reticulum and the Golgi apparatus. In response to extracellular stimuli, the conversion from inactive RAS-GDP to active RAS-GTP further promotes the activation of various signaling pathways, which includes MAPK pathway, PI3K pathway and the Ral-GEFs pathway, among them the MAPK pathway is the best characterized. It is known that RAS-GTP directly binds to RAF protein, recruiting RAF kinase family from cytoplasm to membranes, where they dimerize and become active. The activated RAF subsequently carries out a chain of phosphorylation reactions to its downstream substrates, namely MEK and ERK, and propagates the growth signal. Crystallization Studies of KRAS Protein High Throughput Screen of Crystallization More than 1,000 screen conditions In Vitro Studies of KRAS-targeted Drugs In vitro functional assays are crucial for the practical evaluation of a candidate KRAS-targeted drug in the initial stages of research and development. These assays offer scientific evidence for validating KRAS-targeted drug activity, and providing preliminary evidence that supports therapeutic efficacy. As such, they play a key role in the decision-making process in KRAS-targeted drug candidate selection. KRAS Cellular Assay Medicilon have validated cytotoxicity assays for KRAS mutant cell lines, both 2D and 3D assays could be used for evaluation of KRAS inhibitors.

<comments />