Kirsten rat sarcoma virus, or KRAS, belongs to the Ras family of oncogenes composed of 36 human genes, among which KRAS, NRAS, and HRAS by far play vividly prominent roles in human cancer, participating in cell division, cell differentiation, and the self-destruction of cells (apoptosis). As the most frequently mutated oncogene, KRAS has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies devoted to its involvement in the initiation and progression of cancer diseases. This oncogene encodes a small GTPase transductor protein called K-Ras, a component of the RAS/MAPK biochemical pathway, whose dysregulation has been implicated in various diseases, making it a prime target for medicinal chemistry and drug discovery research. [1]. Targeting critical components of this pathway holds promise for the development of novel therapies for various diseases, including cancer and other disorders driven by aberrant cell signaling.
It should be pointed out that until recently, KRAS has been considered a challenging or even undruggable therapeutic target, with the problem in question obviously stimulating further efforts of chemoinformatics and medicinal chemistry to achieve new noticeable advances in this domain.
Keeping pace with the most pressing research trends, the Life Chemicals team has developed a new RAS/MAPK Signaling Pathway Focused Library of over 1,700 drug-like screening compounds, selected using a 2D Similarity Search against the proprietary HTS Compound Collection.
Customized compound selection and cherry-picking are available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Figure 1. Scheme of RAS/MAPK pathway and examples of compounds from our Screening Library that can inhibit these enzymes.
Background information
K-Ras protein is a GTPase (also known as GTP-binding protein) that catalyzes the conversion of GTP to GDP. As known, there are two types of proteins in humans and other mammals: K-Ras4A and K-Ras4B. It was already mentioned that K-Ras plays an essential role in cell growth, division, and proliferation [2].
RAS/MAPK biochemical cascade is a critical signaling cascade involved in numerous cellular processes. It consists of a chain of proteins that transmit a signal from a receptor on the cell surface to DNA in the cell nucleus, thereby influencing cellular processes such as cell cycle progression, differentiation, and proliferation. [3]. Disorders in the functions and structures of the proteins in this biochemical pathway can lead to uncontrolled cell division and growth, resulting in such malignancies as neuroblastoma, melanoma, pancreatic cancer, Hodgkin lymphoma, lung cancer, colorectal cancer [4], Costello syndrome, Legius syndrome, Noonan syndrome, and cardiofaciocutaneous syndrome [5].
Compound selection
This Screening Library was designed using a 2D Similarity Search against our proprietary HTS Compound Collection to target the RAS/MAPK signaling pathway.
First, a reference set of over 107,000 compounds was prepared utilizing data from the Chembl database. The compounds were pre-filtered based on specific criteria, including IC50, Ki, etc., with their values ranging from 0.1 to 10,000 nM and an inhibition rate greater than 50 %. Next, we conducted a similarity search with a minimum Tanimoto coefficient of 0.8 to select close analogs of active compounds from our catalog.
As a result, we picked out over 1,700 small-molecule screening compounds that are potential inhibitors of various molecular targets in the RAS/MAPK pathway listed below. The average Tanimoto coefficient for the library is 0.89.
- Calmodulin
- CREB-binding protein
- Dual specificity mitogen-activated protein kinase kinase
- Epidermal growth factor receptor erbB1
- Fibroblast growth factor receptor
- GTPase KRas
- MAP kinase ERK
- MAP kinase-interacting serine/threonine-protein kinase MNK
- Myc proto-oncogene protein
- PI3-kinase p110-gamma subunit (PIK3CG)
- Platelet-derived growth factor receptor (PDGFR)
- Retinal dehydrogenase 2 (RALDH2)
- Ribosomal protein S6 kinase
- Serine/threonine-protein kinase RAF
- Son of sevenless homolog 1 (SOS)
Figure 2. Targeted compound distribution within the RAS/MAPK-Pathway Focused Library.
Representative compounds from the RAS/MAPK Signaling Pathway Focused Library
References
- Tanaka N, Lin JJ, Li C, et al. Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS-MAPK Reactivation. Cancer Discov. 2021;11(8):1913-1922.
- Uprety D, Adjei AA. KRAS: From undruggable to a druggable Cancer Target. Cancer Treat Rev. 2020 Sep;89:102070.
- Pudewell S, Wittich C, Kazemein Jasemi NS, Bazgir F, Ahmadian MR. Accessory proteins of the RAS-MAPK pathway: moving from the sideline to the front line. Commun Biol. 2021;4(1):696.
- Drosten M, Barbacid M. Targeting the MAPK Pathway in KRAS-Driven Tumors. Cancer Cell. 2020;37(4):543-550.
- Hebron KE, Hernandez ER, Yohe ME. The RASopathies: from pathogenetics to therapeutics. Dis Model Mech. 2022;15(2):dmm049107.