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KRpep-2d is a K-Ras(G12D) selective inhibitory cyclic peptide that has the potential as the treatment of cancers expressing K-Ras(G12C) mutant.

Peptide Inhibitors
Catalog number
Molecular Formula
Molecular Weight
actinium; [(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(3R,8R,11S,14S,20S,23S,26S,29S,32S,35S,38S)-8-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]-29-[(2R)-butan-2-yl]-20-(carboxymethyl)-26-(hydroxymethyl)-23,32-bis[(4-hydroxyphenyl)methyl]-35-(2-methylpropyl)-2,10,13,19,22,25,28,31,34,37-decaoxo-11-propan-2-yl-5,6-dithia-1,9,12,18,21,24,27,30,33,36-decazatricyclo[,18]hentetracontan-3-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]azanide
Store at -20°C
InChI=1S/C106H179N44O24S2.Ac/c1-7-55(6)79-96(172)144-72(50-151)91(167)141-69(47-56-28-32-58(152)33-29-56)89(165)143-71(49-77(154)155)97(173)149-44-17-27-76(149)94(170)147-78(54(4)5)95(171)145-73(92(168)139-66(24-14-42-131-105(121)122)86(162)137-65(23-13-41-130-104(119)120)84(160)135-63(21-11-39-128-102(115)116)82(158)133-61(80(108)156)19-9-37-126-100(111)112)51-175-176-52-74(98(174)150-45-16-26-75(150)93(169)142-68(46-53(2)3)88(164)140-70(90(166)148-79)48-57-30-34-59(153)35-31-57)146-87(163)67(25-15-43-132-106(123)124)138-85(161)64(22-12-40-129-103(117)118)136-83(159)62(20-10-38-127-101(113)114)134-81(157)60(107)18-8-36-125-99(109)110; /h28-35,53-55,60-76,78-79,107,151-153H,7-27,36-52H2,1-6H3,(H2,108,156)(H,133,158)(H,134,157)(H,135,160)(H,136,159)(H,137,162)(H,138,161)(H,139,168)(H,140,164)(H,141,167)(H,142,169)(H,143,165)(H,144,172)(H,145,171)(H,146,163)(H,147,170)(H,148,166)(H,154,155)(H4,109,110,125)(H4,111,112,126)(H4,113,114,127)(H4,115,116,128)(H4,117,118,129)(H4,119,120,130)(H4,121,122,131)(H4,123,124,132); /q-1; /t55-,60+,61+,62+,63+,64+,65+,66+,67+,68+,69+,70+,71+,72+,73+,74+,75+,76+,78+,79+; /m1./s1
InChI Key
Canonical SMILES
1. Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling
Srinivasaraghavan Kannan, Anthony W Partridge, Hung Yi Kristal Kaan, Nicole Boo, Xiang Yu, Andrea Peier, Nianyu Jason Li, Christopher J Brown, Chunhui Huang, Tomi K Sawyer, Ruchia Duggal, Ahmad Sadruddin, Peter Orth, Shuhui Lim, Feifei Chen, Bhavana Bhatt, David P Lane, Alexander Stoeck, Pooja Gopal, Erjia Wang, Gireedhar Venkatachalam, Raymond J Gonzales, Yu-Chi Angela Juang, Kaustav Biswas, Brian Henry, Tsz Ying Yuen, Michael Garrigou, Simon Ng, Charles W Johannes, Lan Ge, Khong Ming Peh, Nicolas Boyer, Chandra S Verma Chem Sci . 2021 Nov 25;12(48):15975-15987. doi: 10.1039/d1sc05187c.
Macrocyclic peptides have the potential to address intracellular protein-protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons for applying this modality to intracellular targets and specifically for advancing chemical matter to address KRAS, a protein that represents the most common oncogene in human lung, colorectal and pancreatic cancers yet is one of the most challenging targets in human disease. Specifically, we focused on KRpep-2d, an arginine-rich KRAS-binding peptide with a disulfide-mediated macrocyclic linkage and a protease-sensitive backbone. These latter redox and proteolytic labilities obviated cellular activity. Extensive structure-activity relationship studies involving macrocyclic linker replacement, stereochemical inversion, and backbone α-methylation, gave a peptide with on-target cellular activity. However, we uncovered an important generic insight - the arginine-dependent cell entry mechanism limited its therapeutic potential. In particular, we observed a strong correlation between net positive charge and histamine release in anex vivoassay, thus making this series unsuitable for advancement due to the potentially fatal consequences of mast cell degranulation. This observation should signal to researchers that cationic-mediated cell entry - an approach that has yet to succeed in the clinic despite a long history of attempts - carries significant therapy-limiting safety liabilities. Nonetheless, the cell-active molecules identified here validate a unique inhibitory epitope on KRAS and thus provide valuable molecular templates for the development of therapeutics that are desperately needed to address KRAS-driven cancers - some of the most treatment-resistant human malignancies.
2. Investigation of the structural requirements of K-Ras(G12D) selective inhibitory peptide KRpep-2d using alanine scans and cysteine bridging
Ayumu Niida, Masahiro Kamaura, Kotaro Sakamoto, Taiji Asami, Shigekazu Sasaki, Kazuko Yonemori, Tomoya Sameshima, Masahiro Yaguchi Bioorg Med Chem Lett . 2017 Jun 15;27(12):2757-2761. doi: 10.1016/j.bmcl.2017.04.063.
A structure-activity relationship study of a K-Ras(G12D) selective inhibitory cyclic peptide, KRpep-2d was performed. Alanine scanning of KRpep-2d focusing on the cyclic moiety showed that Leu7, Ile9, and Asp12are the key elements for K-Ras(G12D) selective inhibition of KRpep-2d. The cysteine bridging was also examined to identify the stable analog of KRpep-2d under reductive conditions. As a result, the KRpep-2d analog (12) including mono-methylene bridging showed potent K-Ras(G12D) selective inhibition in both the presence and the absence of dithiothreitol. This means that mono-methylene bridging is an effective strategy to obtain a reduction-resistance analog of parent disulfide cyclic peptides. Peptide 12 inhibited proliferation of K-Ras(G12D)-driven cancer cells significantly. These results gave valuable information for further optimization of KRpep-2d to provide novel anti-cancer drug candidates targeting the K-Ras(G12D) mutant.
3. Crystal Structure of a Human K-Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d
Ayumu Niida, Masahiro Kamaura, Kotaro Sakamoto, Satoshi Sogabe, Masanori Miwa, Shigekazu Sasaki, Kazuko Yonemori, Tomoya Sameshima, Jun-Ichi Sakamoto, Yusuke Kamada ACS Med Chem Lett . 2017 May 10;8(7):732-736. doi: 10.1021/acsmedchemlett.7b00128.
The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras(G12D) mutant was determined in complex with GDP and KRpep-2d at 1.25 Å resolution. This structure revealed that the peptide binds near Switch II and allosterically blocks protein-protein interactions with the guanine nucleotide exchange factor. This discovery of a unique binding pocket provides valuable information that will facilitate the design of direct Ras inhibitors.
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