留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

Peilu Song,  Fan Zhao,  Dahong Li,  Jiqiang Qu,  Miao Yao,  Yuan Su,  Hanxun Wang,  Miaomiao Zhou,  Yujie Wang,  Yinli Gao,  Feng Li,  Dongmei Zhao,  Fengjiao Zhang,  Yu Rao,  Mingyu Xia,  Haitao Li,  Jian Wang,  Maosheng Cheng

downloadPDF
文章导航 > 机械工程学报  > 优先出版
Peilu Song, Fan Zhao, Dahong Li, Jiqiang Qu, Miao Yao, Yuan Su, Hanxun Wang, Miaomiao Zhou, Yujie Wang, Yinli Gao, Feng Li, Dongmei Zhao, Fengjiao Zhang, Yu Rao, Mingyu Xia, Haitao Li, Jian Wang, Maosheng Cheng. Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells[J]. 机械工程学报. doi: 10.1016/j.apsb.2022.02.029
引用本文: Peilu Song, Fan Zhao, Dahong Li, Jiqiang Qu, Miao Yao, Yuan Su, Hanxun Wang, Miaomiao Zhou, Yujie Wang, Yinli Gao, Feng Li, Dongmei Zhao, Fengjiao Zhang, Yu Rao, Mingyu Xia, Haitao Li, Jian Wang, Maosheng Cheng. Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells[J]. 机械工程学报. doi: 10.1016/j.apsb.2022.02.029
shu
Peilu Song, Fan Zhao, Dahong Li, Jiqiang Qu, Miao Yao, Yuan Su, Hanxun Wang, Miaomiao Zhou, Yujie Wang, Yinli Gao, Feng Li, Dongmei Zhao, Fengjiao Zhang, Yu Rao, Mingyu Xia, Haitao Li, Jian Wang, Maosheng Cheng. Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.029
Citation: Peilu Song, Fan Zhao, Dahong Li, Jiqiang Qu, Miao Yao, Yuan Su, Hanxun Wang, Miaomiao Zhou, Yujie Wang, Yinli Gao, Feng Li, Dongmei Zhao, Fengjiao Zhang, Yu Rao, Mingyu Xia, Haitao Li, Jian Wang, Maosheng Cheng. Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells[J]. JOURNAL OF MECHANICAL ENGINEERING. doi: 10.1016/j.apsb.2022.02.029
shu

Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

doi: 10.1016/j.apsb.2022.02.029

  • a. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;

  • b. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry Chemical Biology, Tsinghua University, Beijing 100084, China;

  • c. MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China;

  • d. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China;

  • e. School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shengyang 110016, China;

  • f. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China;

  • g. Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China

基金项目: 

This study was supported by National Natural Science Foundation of China (Grant Nos. 81230077, 81872729 and 22077086), Overseas Expertise Introduction Project for Discipline Innovation (Grant No. D20029, China), Program for Innovative Talents of Higher Education of Liaoning (2012520005, China).

详细信息
    通讯作者:

    Mingyu Xia,E-mail:xmywd@vip.sina.com

    Haitao Li,E-mail:lht@tsinghua.edu.cn

    Jian Wang,E-mail:jianwang@syphu.edu.cn

    Maosheng Cheng,E-mail:mscheng@syphu.edu.cn

  • 中图分类号: https://www.sciencedirect.com/science/article/pii/S2211383522000958/pdf?md5=ae19b260f6895fc727bf8964adeabbf8&pid=1-s2.0-S2211383522000958-main.pdf

Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

  • a. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;

  • b. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry Chemical Biology, Tsinghua University, Beijing 100084, China;

  • c. MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China;

  • d. School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China;

  • e. School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shengyang 110016, China;

  • f. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China;

  • g. Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China

Funds: 

This study was supported by National Natural Science Foundation of China (Grant Nos. 81230077, 81872729 and 22077086), Overseas Expertise Introduction Project for Discipline Innovation (Grant No. D20029, China), Program for Innovative Talents of Higher Education of Liaoning (2012520005, China).

    摘要
  • 摘要: The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

     

    Abstract: The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

     

    • HTML全文
    • 参考文献(57)
  • [1] Knaus UG, Bokoch GM. The p21Rac/Cdc42-activated kinases (PAKs). Int J Biochem Cell Biol 1998;30:857-862
    [2] Arias-Romero LE, Chernoff J. A tale of two PAKs. Biol Cell 2008;100:97-108
    [3] Abo A, Qu J, Cammarano MS, Dan C, Fritsch A, Baud V, et al. PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia. EMBO J 1998;17:6527-6540
    [4] Kumar R, Sanawar R, Li X, Li F. Structure, biochemistry, and biology of PAK kinases. Gene 2017;605:20-31
    [5] Rudolph J, Crawford JJ, Hoeflich KP, Wang W. Inhibitors of p21-activated kinases (PAKs). J Med Chem 2015;58:111-129
    [6] Rane CK, Minden A. p21-activated kinase signaling in cancer. Semin Cancer Biol 2019;54:40-49
    [7] Ye DZ, Field J. PAK signaling in cancer. Cell Logist 2012;2:105-116
    [8] Radu M, Semenova G, Kosoff R, Chernoff J. PAK signalling during the development and progression of cancer. Nat Rev Cancer 2014;14:13-25
    [9] Costa TDF, Zhuang T, Lorent J, Turco E, Olofsson H, Masia-Balague M, et al. PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer. Nat Commun 2019;10:1-18
    [10] Dasgupta A, Sierra L, Tsang SV, Kurenbekova L, Patel T, Rajapakshe K, et al. Targeting PAK4 inhibits Ras-mediated signaling and multiple oncogenic pathways in high-risk Rhabdomyosarcoma. Cancer Res 2021;81:199-212
    [11] Tyagi N, Bhardwaj A, Singh AP, McClellan S, Carter JE, Singh S. p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-kappaB pathway. Oncotarget 2014;5:8778-8789
    [12] Tabusa H, Brooks T, Massey AJ. Knockdown of PAK4 or PAK1 inhibits the proliferation of mutant KRAS colon cancer cells independently of RAF/MEK/ERK and PI3K/AKT signaling. Mol Cancer Res 2013;11:109-121
    [13] Yang N, Higuchi O, Ohashi K, Nagata K, Wada A, Kangawa K, et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 1998;393:809-812
    [14] Siu MK, Chan HY, Kong DS, Wong ES, Wong OG, Ngan HY, et al. p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients. Proc Natl Acad Sci U S A 2010;107:18622-18627
    [15] Zhuang T, Zhu J, Li Z, Lorent J, Zhao C, Dahlman-Wright K, Stromblad S. p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells. Oncotarget 2015;6:43853-43868
    [16] Fu X, Feng J, Zeng D, Ding Y, Yu C, Yang B. PAK4 confers cisplatin resistance in gastric cancer cells via PI3K/Akt- and MEK/ERK-dependent pathways. Biosci Rep 2014;34:e00094
    [17] Mohammad RM, Li Y, Muqbil I, Aboukameel A, Senapedis W, Baloglu E, et al. Targeting Rho GTPase effector p21 activated kinase 4 (PAK4) suppresses p-Bad-microRNA drug resistance axis leading to inhibition of pancreatic ductal adenocarcinoma proliferation. Small GTPases 2019;10:367-377
    [18] Abril-Rodriguez G, Torrejon DY, Liu W, Zaretsky JM, Nowicki TS, Tsoi J, et al. PAK4 inhibition improves PD-1 blockade immunotherapy. Nat Cancer 2019;1:46-58
    [19] Gajewski TF, Fessler J. PAK4 as a cancer immune-evasion target. Nat Cancer 2020;1:18-19
    [20] Ma W, Wang Y, Zhang R, Yang F, Zhang D, Huang M, et al. Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma. Nat Cancer 2020;2:83-97
    [21] Staben ST, Feng JA, Lyle K, Belvin M, Boggs J, Burch JD, et al. Back pocket flexibility provides group II p21-activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors. J Med Chem 2014;57:1033-1045
    [22] Guo C, McAlpine I, Zhang J, Knighton DD, Kephart S, Johnson MC, et al. Discovery of pyrroloaminopyrazoles as novel PAK inhibitors. J Med Chem 2012;55:4728-4739
    [23] Park JK, Kim S, Han YJ, Kim SH, Kang NS, Lee H, et al. The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor. Bioorg Med Chem Lett 2016;26:2580-2583
    [24] Crawford JJ, Hoeflich KP, Rudolph J. p21-Activated kinase inhibitors:a patent review. Expert Opin Ther Pat 2012;22:293-310
    [25] Murray BW, Guo C, Piraino J, Westwick JK, Zhang C, Lamerdin J, et al. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci U S A 2010;107:9446-9451
    [26] Senapedis W, Landesman Y, Schenone M, Karger B, Wu S, Shacham S, et al. Identification of novel small molecules as selective PAK4 allosteric modulators (PAMs) by stable isotope labeling of amino acids in cells (SILAC). Eur J Cancer 2014;50:156
    [27] Mitchell S, Zhang P, Cannon M, Beaver L, Lehman A, Harrington B, et al. Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation. J Hematol Oncol 2021;14:101
    [28] Aboukameel A, Muqbil I, Senapedis W, Baloglu E, Landesman Y, Shacham S, et al. Novel p21-activated kinase 4 (PAK4) allosteric modulators overcome drug resistance and stemness in pancreatic ductal adenocarcinoma. Mol cancer ther 2017;16:76-87
    [29] Hao C, Zhao F, Song H, Guo J, Li X, Jiang X, et al. Structure-based design of 6-chloro-4-aminoquinazoline-2-carboxamide derivatives as potent and selective p21-activated kinase 4 (PAK4) inhibitors. J Med Chem 2018;61:265-285
    [30] Guo J, Zhao F, Yin W, Zhu M, Hao C, Pang Y, et al. Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors. Eur J Med Chem 2018;155:197-209
    [31] Hao C, Huang W, Li X, Guo J, Chen M, Yan Z, et al. Development of 2,4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy. Eur J Med Chem 2017;131:1-13
    [32] Song S, Li X, Guo J, Hao C, Feng Y, Guo B, et al. Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors. Org Biomol Chem 2015;13:3803-3818
    [33] Zuccotto F, Ardini E, Casale E, Angiolini M. Through the "gatekeeper door":exploiting the active kinase conformation. J Med Chem 2010;53:2681-2694
    [34] Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, et al. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl) ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy) quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem 2006;49:6465-6488
    [35] Ballard P, Bradbury RH, Harris CS, Hennequin LF, Hickinson M, Johnson PD, et al. Inhibitors of epidermal growth factor receptor tyrosine kinase:Novel C-5 substituted anilinoquinazolines designed to target the ribose pocket. Bioorg Med Chem Lett 2006;16:1633-1637
    [36] Liao JJ. Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J Med Chem 2007;50:409-424
    [37] Crawford JJ, Lee W, Aliagas I, Mathieu S, Hoeflich KP, Zhou W, et al. Structure-guided design of group I selective p21-activated kinase inhibitors. J Med Chem 2015;58:5121-5136
    [38] Blaquiere N, Castanedo GM, Burch JD, Berezhkovskiy LM, Brightbill H, Brown S, et al. Scaffold-hopping approach to discover potent, selective, and efficacious inhibitors of NF-kappaB inducing kinase. J Med Chem 2018;61:6801-6813
    [39] Talele TT. Acetylene group, friend or foe in medicinal chemistry. J Med Chem 2020;63:5625-5663
    [40] Hennequin LF, Allen J, Breed J, Curwen J, Fennell M, Green TP, et al. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem 2006;49:6465-6488
    [41] Ryu BJ, Kim S, Min B, Kim KY, Lee JS, Park WJ, et al. Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor. Cancer Lett 2014;349:45-50
    [42] Callow MG, Clairvoyant F, Zhu S, Schryver B, Whyte DB, Bischoff JR, et al. Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. J Biol Chem 2002;277:550-558
    [43] Yun CY, You ST, Kim JH, Chung JH, Han SB, Shin EY, et al. p21-activated kinase 4 critically regulates melanogenesis via activation of the CREB/MITF and β-Catenin/MITF pathways. J Invest Dermatol 2015;135:1385-1394
    [44] Cai S, Ye Z, Wang X, Pan Y, Weng Y, Lao S, et al. Overexpression of P21-activated kinase 4 is associated with poor prognosis in non-small cell lung cancer and promotes migration and invasion. J Exp Clin Cancer Res 2015;34:48
    [45] Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med 2019;11:eaaw8412
    [46] Osmani N, Goetz JG. Multiscale imaging of metastasis in zebrafish. Trends Cancer 2019;5:766-778
    [47] Zon LI, Peterson RT. In vivo drug discovery in the zebrafish. Nat Rev Drug Discov 2005;4:35-44
    [48] Oft M, Heider K-H, Beug H. TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998;8:1243-1252
    [49] Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, et al. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest 2007;117:1305-1313
    [50] Padua D, Zhang XHF, Wang Q, Nadal C, Gerald WL, Gomis RR, et al. TGF beta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008;133:66-77
    [51] Siegel PM, Shu WP, Cardiff RD, Muller WJ, Massague J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. P Natl Acad Sci U S A 2003;100:8430-8435
    [52] Fan Y, Wang X, Li Y, Zhao X, Zhou J, Ma X, et al. PAK4 enhances TGF-beta 1-induced epithelial-mesenchymal transition through activating beta-catenin signaling pathway in renal tubular epithelial cells. Int J Clin Exp Patho 2018;11:3026-3035
    [53] Jin R, Liu W, Menezes S, Yue F, Zheng M, Kovacevic Z, et al.The metastasis suppressor NDRG1 modulates the phosphorylation and nuclear translocation of beta-catenin through mechanisms involving FRAT1 and PAK4. J Cell Sci 2014;127:3116-3130
    [54] Kesanakurti D, Maddirela D, Banasavadi-Siddegowda YK, Lai TH, Qamri Z, Jacob NK, et al. A novel interaction of PAK4 with PPARgamma to regulate Nox1 and radiation-induced epithelial-to-mesenchymal transition in glioma. Oncogene 2017;36:5309-5320
    [55] Chen T, Wang T, Liang W, Zhao Q, Yu Q, Ma CM, et al. PAK4 phosphorylates fumarase and blocks TGFbeta-induced cell growth arrest in lung cancer cells. Cancer Res 2019;79:1383-1397
    [56] Huang J, Chen Z, Lai Z, Liu Y, Yu D, Wu L, et al. Kaempferol ameliorates the regulatory effects of PVT1/miR-214 on epithelial-mesenchymal transition through the PAK4/beta-catenin axis in SRA01/04 cells. Future Med Chem 2021;13:613-623
    [57] Burlingham BT, Widlanski TS. An intuitive look at the relationship of Ki and IC50:a more general use for the Dixon Plot. J Chem Educ 2003;80:214-218
    • 相关文章
    • 施引文献
  • 资源附件(0)
  • 加载中
WeChat 点击查看大图
计量
  • 文章访问数:  46
  • HTML全文浏览量:  25
  • PDF下载量:  0
  • 被引次数: 0
出版历程
  • 收稿日期:  2021-11-03
  • 修回日期:  2022-01-26
  • 录用日期:  2022-02-10
  • 网络出版日期:  2023-03-17

目录

    /

    返回文章
    返回

    Copyright © 2008 北京仁和汇智信息技术有限公司

    地址：邮政编码：100101

    电话：010-84988317，84988356，84988357传真：021-64253812Email：syzt@vip.163.com

    京公网安备 11010502036328号　京ICP备17033152号

    本系统由 北京仁和汇智信息技术有限公司 开发