Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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Inhibitors of G12C Mutant Ras Proteins for the Treatment of Cancers Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States (RasGRP). In contrast to GEFs, GAPs downregulate the GTPase activity of Ras by stimulating the slow rate of GTP hydrolysis, enabling the population of Ras in its inactive GDPbound form in vivo. Several different Ras GAPs, including p120GAP, neurofibromin1 (NF1), and the GAP1 family have structural similarity in the RasGAP catalytic core domain. The Ras proteins consist of 188−189 amino acids and have a highly conserved N-terminal G-domain containing the p-loop region, which binds to nucleotide, and the switch I and switch II regions that are essential for regulation and effector protein interactions. The p-loop and NKXD motifs of the HRas primarily interact with its GTP and GDP ligands, and Switches I and II of HRas interact with its regulatory and effector proteins. The HRas motifs are conserved in hERas and mERas, which is due to the combinational feature of the p-loop with the Switch II of HRas that dictates the binding features of HRas with GTP and GDP. These unique p-loop and Switch II residues of hERas are also conserved in mERas, with the exception that mERas possesses Asp100 instead of the hERas Ala100. Unlike the hERas Switch II residue, mERas has an additional hERas specific Switch II residue Ser97. The best characterized effector of Ras is the serine/ threonine kinase Raf, which regulates the activity of the mitogen-activate protein kinase (MAPK) pathway. The phosphoinositide 3-kinase (PI3K) pathway is a very important downstream effector pathway of Ras with the p110 catalytic subunit of the class I PI3K interacting with Ras. Glycine to cysteine mutations at residue 12 of Ras (12C mutation) is generated from a G.C to T.A base transversion at codon 12. The G12C mutation is enriched in KRas mutant nonsmall lung cancer, which is associated with the DNA adducts formed by tobacco smoke. Trapping the K-Ras protein in an active state leads to abnormally high concentrations of GTP-bound K-Ras; this results in up-regulation of downstream pathways and unregulated cell proliferation and tumor growth. The KRas mutations are found in many cancers including uterine cancer, bile duct, multiple myeloma, stomach cancer, diffuse large B cell lymphoma, cutaneous squamous cell carcinoma, cervical cancer, and so forth. There are no inhibitors of G12C mutant Ras proteins that have been approved for therapeutic use; however, there are two clinical studies recruiting for subjects to evaluate the KRas G12C mutant in cancer cells (https://clinicaltrials.gov/ct2/ results?cond=G12C&term=&cntry=&state=&city=&dist=). Compounds of this Patent Highlight possess antitumor activity and are useful in inhibiting the dysregulation of cellular proliferation in malignant diseases and are acting as inhibitors of G12C mutant Ras proteins.
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Title. Heteroaryl Compounds That Inhibit G12C Mutant Ras Proteins Patent Application Number. WO 2018/206539 A1 Publication Date. November 15, 2018 Priority Application. US 62/504,638 Priority Date. May 11, 2017 Inventors. Kettle, J. G.; Bagal, S. K.; Boyd, S.; Eather-Ton, A. J.; Fillery, S. M.; Robb, G. R.; Raubo, P. A. Assignee Company. AstraZeneca AB Disease Area. Cancer Biological Target. G12C mutant Ras proteins Summary. Proteins containing single amino acid mutations are expressed in a large number of cancerous tissues. The Ras family of small GTPases, which are a family of hydrolase enzymes that bind and hydrolyze guanosine triphosphate (GTP), consists of several GTP binding proteins that include Harvey Ras (HRas), Kirsten Ras (KRas), and Neuroblastoma Ras (NRas). These Ras proteins function as a molecular switch that cycles between inactive GDP-bound and active GTPbound forms. Within the Ras family of proteins, the KRas is the most frequently mutated isoform, which is present in 22% of all tumors and 90% of pancreatic tumors. The KRas protein was discovered over 30 years ago and has been termed “undruggable” due to the failure to design a drug that would successfully target the mutant gene. The KRas gene is the most mutated oncogene in human cancers, and G12C is the most frequent mutation of KRas, which substitute the amino acid cysteine for glycine at position 12 in the KRas protein. Regulatory proteins of Ras include guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). GEFs upregulate the function of Ras by accelerating the intrinsically slow rate of the guanine nucleotide exchange (GNE) of Ras, which is necessary to generate the active GTPbound state of Ras. The GDP/GTP cycle of Ras is tightly regulated in cells by GEFs such as Son of Sevenless (SOS1 and SOS2), which promote the exchange of GDP for GTP. GAPs such as NF-1 and p120RasGAP stimulate the intrinsic GTPase activity in Ras hydrolyzation of GTP to GDP. There are several GEF proteins that target the Ras family of GTPases, which include Ras guanine-nucleotide-release factor (RasGRF) and the Ras guanyl nucleotide-releasing protein © XXXX American Chemical Society
Received: November 24, 2018
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DOI: 10.1021/acsmedchemlett.8b00576 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Definitions. Ring A = aryl, monocyclic heteroaryl, and bicyclic heteroaryl. R 1 = C 1−4 alkyl, halo, hydroxy, C 1−4 alkoxy, cyano, C1−3fluoroalkoxy, and so forth. b = 0, 1, 2, or 3. Y = CR15R16, CO. R2 = H, cyano, halo, C1−4alkyl, C1−4alkoxy, and acetylenyl. R3 = H, C1−3fluoroalkyl, OR26, SR30, or C(O)R31. R4 = R5 = H or Me. R6 = H or CH2NMe2. Key Structures.
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1. Tsioufis, C.; Andrikou, I.; Siasos, G.; Tousoulis, D.; Filis, K. Curr. Opin. Pharmacol. 2018, 39, 35. 2. Pant, S.; Hubbard, J.; Martinelli, E.; Bekaii-Saab, T. Crit. Rev. Oncol. Hemat. 2018, 130, 78. 3. Kidger, A. M.; Cook, S. J.; Sipthorp J. Pharmacol. Ther. 2018, 187, 45. 4. Nabet, B.; Gray, N. S. Biochemistry. 2018, 57, 2289.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Robert B. Kargbo: 0000-0002-5539-6343 Notes
The author declares no competing financial interest.
Biological Assay. The KRasG12C functional assay was used to evaluate compounds in this Patent Highlight. The IC50 values were calculated from normalized dose−response FRET data curve fitted in Genedata screener. Biological Data. The Table below shows functional and binding assay results, which evaluates compounds in this Patent Highlight for inhibition of the KRasG12C mutant proteins. Recent Review Articles. B
DOI: 10.1021/acsmedchemlett.8b00576 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
