Research progress of KRAS inhibitors
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摘要:
KRAS蛋白是由克里斯汀鼠肉瘤病毒基因（Kirsten rat sarcoma viral oncogene，KRAS）编码的一种小GTP酶，参与细胞的增殖、分化、迁移和凋亡等活动，被认为是调控细胞生命周期的信号开关。然而KRAS基因容易发生突变导致下游信号通路的过度激活，是肿瘤疾病发生发展的重要因素。KRAS蛋白常见突变位点包括G12、G13和Q61，不同的突变体对蛋白生理功能的影响和主要肿瘤疾病类型具有差异性。KRAS蛋白由于其光滑的表面和对核苷酸的高亲和力一度被认为是“不可成药”的靶点。直到靶向KRAS G12C共价抑制剂索托雷塞（sotorasib）和阿达格拉西布（adagrasib）的上市才打破了KRAS不可成药的现状。文章就KRAS蛋白的结构和功能以及直接靶向KRAS G12C、KRAS G12D、KRAS G12R、KRAS G12S和泛KRAS抑制剂的研究现状、面临的挑战进行综述，旨在为KRAS抑制剂的发展提供有益参考。
Abstract:KRAS protein, a small GTPase encoded by the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene, is involved in cell proliferation, differentiation, migration and cell survival, and is known as a regulatory switch for the cell life cycle. However, KRAS gene is prone to mutation, leading to hyperactivation of its downstream signaling pathways, and has a vital role in driving tumorigenesis. KRAS mutations predominantly take place at residue G12, G13 or Q61, and different mutants have varying effects on protein physiological functions and tumor types. Due to its smooth surface and high affinity for nucleotides, KRAS had been considered to be “undruggable” until the launch of selective KRAS G12C inhibitors sotorasib and adagrasib, which broke the dogma. This review introduces the structure and functions of KRAS, as well as the status and progress of inhibitors directly targeting KRAS mutants (G12C, G12D, G12R, G12S) and pan-KRAS inhibitors, aiming to provide some insightful reference for the development of KRAS inhibitors.
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Keywords:
- RAS /
- KRAS /
- KRAS inhibitors /
- antitumor
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[1] Rhett JM, Khan I, O’Bryan JP. Biology, pathology, and therapeutic targeting of RAS[J]. Adv Cancer Res, 2020, 148: 69-146.
[2] Yoo BH, Khan IA, Koomson A, et al. Oncogenic ras-induced downregulation of atg12 is required for survival of malignant intestinal epithelial cells[J]. Autophagy, 2017, 14(1): 134-151 doi: 10.1080/01902140120175
[3] Cazzanelli G, Pereira F, Alves S, et al. The yeast saccharomyces cerevisiae as a model for understanding ras proteins and their role in human tumorigenesis[J]. Cells, 2018, 7(2): 14 doi: 10.1186/s13045-022-01375-4
[4] Kulkarni AM, Kumar V, Parate S, et al. Identification of new KRAS G12D inhibitors through computer-aided drug discovery methods[J]. Int J Mol Sci, 2022, 23(3): 1309. doi: 10.3390/ijms23031309
[5] O’Bryan JP. Pharmacological targeting of RAS: recent success with direct inhibitors[J]. Pharmacol Res, 2019, 139: 503-511. doi: 10.1016/j.phrs.2018.10.021
[6] Huang L, Guo Z, Wang F, et al. KRAS mutation: from undruggable to druggable in cancer[J]. Signal Transduct Target Ther, 2021, 6(1): 386. doi: 10.1038/s41392-021-00780-4
[7] Ostrem JML, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design[J]. Nat Rev Drug Discovery, 2016, 15(11): 771-785. doi: 10.1038/nrd.2016.139
[8] Nan X, Tamgüney TM, Collisson EA, et al. RAS-GTP dimers activate the mitogen-activated protein kinase (MAPK) pathway[J]. Proc Natl Acad Sci U S A, 2015, 112(26): 7996-8001. doi: 10.1073/pnas.1509123112
[9] Haider K, Sharma A, Yar MS, et al. Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design[J]. Expert Opin Drug Discov, 2022, 17(3): 247-257. doi: 10.1080/17460441.2022.2029842
[10] Gao L, Shen W. Light at the end of the tunnel: clinical features and therapeutic prospects of KRAS mutant subtypes in non-small-cell lung cancer[J]. Front Genet, 2022, 13: 890247. doi: 10.3389/fgene.2022.890247
[11] Ferreira A, Pereira F, Reis C, et al. Crucial role of oncogenic KRAS mutations in apoptosis and autophagy regulation: therapeutic implications[J]. Cells, 2022, 11(14): 2183. doi: 10.3390/cells11142183
[12] Lu H, Martí J. Predicting the conformational variability of oncogenic GTP-bound G12D mutated KRAS-4B proteins at zwitterionic model cell membranes[J]. Nanoscale, 2022, 14(8): 3148-3158. doi: 10.1039/D1NR07622A
[13] Lee KY, Enomoto M, Gebregiworgis T, et al. Oncogenic KRAS G12D mutation promotes dimerization through a second, phosphatidylserine–dependent interface: a model for KRAS oligomerization[J]. Chem Sci, 2021, 12(38): 12827-12837. doi: 10.1039/D1SC03484G
[14] Zhu C, Guan X, Zhang X, et al. Targeting KRAS mutant cancers: from druggable therapy to drug resistance[J]. Mol Cancer, 2022, 21(1): 159. doi: 10.1186/s12943-022-01629-2
[15] Zinatizadeh MR, Momeni SA, Zarandi PK, et al. The role and function of RAS-association domain family in cancer: a review[J]. Genes Dis, 2019, 6(4): 378-384. doi: 10.1016/j.gendis.2019.07.008
[16] Damnernsawad A, Kong G, Wen Z, et al. KRAS is required for adult hematopoiesis[J]. Stem Cells, 2016, 34(7): 1859-1871. doi: 10.1002/stem.2355
[17] Abdelkarim H, Leschinsky N, Jang H, et al. The dynamic nature of the K-RAS/calmodulin complex can be altered by oncogenic mutations[J]. Curr Opin Struct Biol, 2021, 71: 164-170. doi: 10.1016/j.sbi.2021.06.008
[18] Zdanov S, Mandapathil M, Abu Eid R, et al. Mutant KRAS conversion of conventional T cells into regulatory T cells[J]. Cancer Immunol Res, 2016, 4(4): 354-365. doi: 10.1158/2326-6066.CIR-15-0241
[19] Prior IA, Hood FE, Hartley JL. The frequency of RAS mutations in cancer[J]. Cancer Res, 2020, 80(14): 2969-2974. doi: 10.1158/0008-5472.CAN-19-3682
[20] Hunter JC, Manandhar A, CarRASco MA, et al. Biochemical and structural analysis of common cancer-associated KRAS mutations[J]. Mol Cancer Res, 2015, 13(9): 1325-1335. doi: 10.1158/1541-7786.MCR-15-0203
[21] Vatansever S, Erman B, Gümüş ZH. Oncogenic G12D mutation alters local conformations and dynamics of K-RAS[J]. Sci Rep, 2019, 9(1): 11730. doi: 10.1038/s41598-019-48029-z
[22] Gray JL, von Delft F, Brennan PE. Targeting the small GTPase superfamily through their regulatory proteins[J]. Angew Chem Int Ed, 2020, 59(16): 6342-6366. doi: 10.1002/anie.201900585
[23] Désage A-L, Léonce C, Swalduz A, et al. Targeting KRAS mutant in non-small cell lung cancer: Novel insights into therapeutic strategies[J]. Front Oncol, 2022, 12: 796832. doi: 10.1002/prot.24786
[24] Lam KK, Wong SH, Cheah PY. Targeting the ‘undruggable’ driver protein, KRAS, in epithelial cancers: Current perspective[J]. Cells, 2023, 12(4): 631. doi: 10.1093/abbs/gmv100
[25] Prakash P, Hancock JF, Gorfe AA. Binding hotspots on K-RAS: Consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis[J]. Proteins, 2015, 83(5): 898-909. doi: 10.3389/fonc.2022.796832
[26] McCarthy M, Prakash P, Gorfe AA. Computational allosteric ligand binding site identification on RAS proteins[J]. Acta Biochim Biophys Sin, 2016, 48(1): 3-10. doi: 10.3390/cells12040631
[27] Ostrem JM, Peters U, Sos ML, et al. K-RAS(G12C) inhibitors allosterically control GTP affinity and effector interactions[J]. Nature, 2013, 503(7477): 548-551. doi: 10.1038/nature12796
[28] Patricelli MP, Janes MR, Li LS, et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state[J]. Cancer Discov, 2016, 6(3): 316-329. doi: 10.1158/2159-8290.CD-15-1105
[29] Janes MR, Zhang J, Li LS, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor[J]. Cell, 2018, 172 (3): 578-589. e517.
[30] Wang J, Martin-Romano P, Cassier P, et al. Phase I study of JNJ-74699157 in patients with advanced solid tumors harboring the KRAS G12C mutation[J]. The Oncologist, 2022, 27(7): 536-e553. doi: 10.1093/oncolo/oyab080
[31] Erlanson DA Webster KR. Targeting mutant KRAS[J]. Curr Opin Chem Biol, 2021, 62: 101-108. doi: 10.1016/j.cbpa.2021.02.010
[32] Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity[J]. Nature, 2019, 575(7781): 217-223. doi: 10.1038/s41586-019-1694-1
[33] Fell JB, Fischer JP, Baer BR, et al. Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer[J]. J Med Chem, 2020, 63(13): 6679-6693. doi: 10.1021/acs.jmedchem.9b02052
[34] Wang H, Chi L, Yu F, et al. Annual review of KRAS inhibitors in 2022[J]. Eur J Med Chem, 2023, 249: 115124. doi: 10.1016/j.ejmech.2023.115124
[35] Laurent P-A, Milic M, Quevrin C, et al. KRASG12C inhibition using MRTX1257: a novel radio-sensitizing partner[J]. J Transl Med, 2023, 21(1): 773. doi: 10.1186/s12967-023-04619-0
[36] Xu J, Lim N-K, Timmerman JC, et al. Second-generation atroposelective synthesis of KRAS G12C covalent inhibitor GDC-6036[J]. Org Lett, 2023, 25(19): 3417-3422. doi: 10.1021/acs.orglett.3c00961
[37] Sacher A, LoRusso P, Patel MR, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation[J]. N Engl J Med, 2023, 389(8): 710-721. doi: 10.1056/NEJMoa2303810
[38] Zeng M, Lu J, Li L, et al. Potent and selective covalent quinazoline inhibitors of KRAS G12C[J]. Cell Chem Biol, 2017, 24 (8): 1005-1016. e1003.
[39] Imaizumi T, Akaiwa M, Abe T, et al. Discovery and biological evaluation of 1-{2, 7-diazaspiro[3.5]nonan-2-yl}prop-2-en-1-one derivatives as covalent inhibitors of KRAS G12C with favorable metabolic stability and anti-tumor activity[J]. Bioorg Med Chem, 2022, 71: 116949. doi: 10.1016/j.bmc.2022.116949
[40] Peng SB, Si C, Zhang Y, et al. Abstract 1259: preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor[J]. Cancer Res, 2021, 81(13_Supplement): 1259. doi: 10.1158/1538-7445.AM2021-1259
[41] Weiss A, Lorthiois E, Barys L, et al. Discovery, preclinical characterization, and early clinical activity of JDQ443, a structurally novel, potent, and selective covalent oral inhibitor of KRASG12C[J]. Cancer Discov, 2022, 12(6): 1500-1517. doi: 10.1158/2159-8290.CD-22-0158
[42] Cappuzzo F, Castro G, Kang JH, et al. KontRASt-02: a phase III trial investigating the efficacy and safety of the KRASG12C inhibitorJDQ443 vs. Docetaxel in patients with previously treated, locally advanced or metastatic, KRAS G12C-mutated nsclc[J]. Int J Radiat Oncol, 2024, 118(1): e14.
[43] Lorthiois E, Gerspacher M, Beyer KS, et al. JDQ443, a structurally novel, pyrazole-based, covalent inhibitor of KRASG12C for the treatment of solid tumors[J]. J Med Chem, 2022, 65(24): 16173-16203. doi: 10.1021/acs.jmedchem.2c01438
[44] Bröker J, Waterson AG, Smethurst C, et al. Fragment optimization of reversible binding to the switch II pocket on KRAS leads to a potent, in vivo active KRASG12C inhibitor[J]. J Med Chem, 2022, 65(21): 14614-14629. doi: 10.1021/acs.jmedchem.2c01120
[45] Song Z, Lou L, Fan G, et al. Identification of novel pyrrolo[2, 3-d]pyrimidine-based KRAS G12C inhibitors with anticancer effects[J]. Eur J Med Chem, 2023, 245 (Pt 1): 114907.
[46] Hallin J, Bowcut V, Calinisan A, et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor[J]. Nat Med, 2022, 28(10): 2171-2182. doi: 10.1038/s41591-022-02007-7
[47] Yu Z, He X, Wang R, et al. Simultaneous covalent modification of K-RAS(G12D) and K-RAS(G12C) with tunable oxirane electrophiles[J]. J Am Chem Soc, 2023, 145(37): 20403-20411. doi: 10.1021/jacs.3c05899
[48] Wang X, Allen S, Blake JF, et al. Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor[J]. J Med Chem, 2021, 65(4): 3123-3133.
[49] Ji X, Li Y, Kong X, et al. Discovery of prodrug of MRTX1133 as an oral therapy for cancers with KRASG12D mutation[J]. ACS Omega, 2023, 8(7): 7211-7221. doi: 10.1021/acsomega.3c00329
[50] Cheng H, Li P, Chen P, et al. Structure-based design and synthesis of potent and selective KRAS G12D inhibitors[J]. ACS Med Chem Lett, 2023, 14(10): 1351-1357. doi: 10.1021/acsmedchemlett.3c00245
[51] Mao Z, Xiao H, Shen P, et al. KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge[J]. Cell Discov, 2022, 8(1): 5. doi: 10.1038/s41421-021-00368-w
[52] Li L, Liu J, Yang Z, et al. Discovery of thieno[2, 3-d]pyrimidine-based KRAS G12D inhibitors as potential anticancer agents via combinatorial virtual screening[J]. Eur J Med Chem, 2022, 233: 114243. doi: 10.1016/j.ejmech.2022.114243
[53] Kazi A, Ranjan A, Kumar MVV, et al. Discovery of KRB-456, a KRAS G12D switch-I/II allosteric pocket binder that inhibits the growth of pancreatic cancer patient-derived tumors[J]. Cancer Commun, 2023, 3(12): 2623-2639.
[54] Chiang J, Li X, Liu APY, et al. Tectal glioma harbors high rates of KRAS G12R and concomitant KRAS and braf alterations[J]. Acta Neuropathol, 2019, 139(3): 601-602.
[55] Bannoura SF, Khan HY, Azmi AS. KRAS G12D targeted therapies for pancreatic cancer: has the fortress been conquered[J]? Front Oncol, 2022, 12: 1013902. doi: 10.3389/fonc.2022.1013902
[56] Chen H, Smaill JB, Liu T, et al. Small-molecule inhibitors directly targeting KRAS as anticancer therapeutics[J]. J Med Chem, 2020, 63(23): 14404-14424. doi: 10.1021/acs.jmedchem.0c01312
[57] Zhang Z, Morstein J, Ecker AK, et al. Chemoselective covalent modification of K-RAS(G12R) with a small molecule electrophile[J]. J Am Chem Soc, 2022, 144(35): 15916-15921. doi: 10.1021/jacs.2c05377
[58] Gao Q, Ouyang W, Kang B, et al. Selective targeting of the oncogenic KRAS G12S mutant allele by crispr/cas9 induces efficient tumor regression[J]. Theranostics, 2020, 10(11): 5137-5153. doi: 10.7150/thno.42325
[59] Zhang Z, Guiley KZ, Shokat KM. Chemical acylation of an acquired serine suppresses oncogenic signaling of K-RAS(G12S)[J]. Nat Chem Biol, 2022, 18(11): 1177-1183. doi: 10.1038/s41589-022-01065-9
[60] Kessler D, Gmachl M, Mantoulidis A, et al. Drugging an undruggable pocket on KRAS[J]. Proc Natl Acad Sci U S A, 2019, 116(32): 15823-15829. doi: 10.1073/pnas.1904529116
[61] Welsch ME, Kaplan A, Chambers JM, et al. Multivalent small-molecule pan-RAS inhibitors[J]. Cell, 2017, 168 (5): 878-889. e829.
[62] Kim D, Herdeis L, Rudolph D, et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth[J]. Nature, 2023, 619(7968): 160-166. doi: 10.1038/s41586-023-06123-3
[63] Matsubara H, Miyoshi H, Kakizaki F, et al. Efficacious combination drug treatment for colorectal cancer that overcomes resistance to KRAS G12C inhibitors[J]. Mol Cancer Ther, 2023, 22(4): 529-538. doi: 10.1158/1535-7163.MCT-22-0411
[64] Wu X, Upadhyaya P, Villalona-Calero MA, et al. Inhibition of RAS-effector interactions by cyclic peptides[J]. Med Chem Comm, 2013, 4(2): 378-382. doi: 10.1039/C2MD20329D
[65] Upadhyaya P, Qian Z, Habir NAA, et al. Direct RAS inhibitors identified from a structurally rigidified bicyclic peptide library[J]. Tetrahedron, 2014, 70(42): 7714-7720. doi: 10.1016/j.tet.2014.05.113
[66] Sakamoto K, Kamada Y, Sameshima T, et al. K-RAS(G12D)-selective inhibitory peptides generated by random peptide T7 phage display technology[J]. Biochem Biophys Res Commun, 2017, 484(3): 605-611. doi: 10.1016/j.bbrc.2017.01.147
[67] Sakamoto K, Lin B, Nunomura K, et al. The K-RAS(G12D)-inhibitory peptide KS-58 suppresses growth of murine CT26 colorectal cancer cell-derived tumors[J]. Sci Rep, 2022, 12(1):8121.
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