Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold

被引：4
作者：
Yang, Dezhi [1 ]
Tong, Dongdong [2 ]
Zhang, Qian [1 ]
Wang, Yongtao [1 ]
Sun, Jing [3 ]
Zhang, Fenghe [2 ]
Zhao, Guisen [1 ]
机构：
[1] Shandong Univ, Dept Med Chem, Key Lab Chem Biol, Minist Educ,Sch Pharmaceut Sci, Jinan, Shandong, Peoples R China
[2] Shandong Univ, Dept Oral & Maxillofacial Surg, Shandong Prov Key Lab Oral Tissue Regenerat, Sch Stomatol, Jinan, Shandong, Peoples R China
[3] Shandong Univ, Shandong Prov Key Lab Oral Tissue Regenerat, Sch Stomatol, Dept Bone Metab, Jinan, Shandong, Peoples R China
来源：
CHEMICAL BIOLOGY & DRUG DESIGN | 2017年 / 90卷 / 05期
基金：
中国国家自然科学基金;
关键词：
Akt1; inhibitors; antiproliferative activity; GSK3; indole scaffold; MITSUNOBU REACTIONS; BREAST-CANCER; DISCOVERY; THERAPY; KINASE; POTENT; TUMORS;
D O I：
10.1111/cbdd.13000
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC-3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3 protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC50 value of 3.1 +/- 0.1m than positive control (15.5 +/- 0.4m). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.
引用
收藏
页码：791 / 803
页数：13
相关论文
共 21 条
  • [1] Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases
    Addie, Matt
    Ballard, Peter
    Buttar, David
    Crafter, Claire
    Currie, Gordon
    Davies, Barry R.
    Debreczeni, Judit
    Dry, Hannah
    Dudley, Philippa
    Greenwood, Ryan
    Johnson, Paul D.
    Kettle, Jason G.
    Lane, Clare
    Lamont, Gillian
    Leach, Andrew
    Luke, Richard W. A.
    Morris, Jeff
    Ogilvie, Donald
    Page, Ken
    Pass, Martin
    Pearson, Stuart
    Ruston, Linette
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (05) : 2059 - 2073
  • [2] Prognostic significance of Akt, phospho-Akt and BAD expression in primary breast cancer
    Al-Bazz, Yousif O.
    Underwood, James C. E.
    Brown, Barry L.
    Dobson, Pauline R. M.
    [J]. EUROPEAN JOURNAL OF CANCER, 2009, 45 (04) : 694 - 704
  • [3] Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors
    Blake, James F.
    Xu, Rui
    Bencsik, Josef R.
    Xiao, Dengming
    Kallan, Nicholas C.
    Schlachter, Stephen
    Mitchell, Ian S.
    Spencer, Keith L.
    Banka, Anna L.
    Wallace, Eli M.
    Gloor, Susan L.
    Martinson, Matthew
    Woessner, Richard D.
    Vigers, Guy P. A.
    Brandhuber, Barbara J.
    Liang, Jun
    Safina, Brian S.
    Li, Jun
    Zhang, Birong
    Chabot, Christine
    Do, Steven
    Lee, Leslie
    Oeh, Jason
    Sampath, Deepak
    Lee, Brian B.
    Lin, Kui
    Liederer, Bianca M.
    Skelton, Nicholas J.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (18) : 8110 - 8127
  • [4] Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis
    Cully, M
    You, H
    Levine, AJ
    Mak, TW
    [J]. NATURE REVIEWS CANCER, 2006, 6 (03) : 184 - 192
  • [5] Novel, potent and selective cyclin D1/CDK4 inhibitors:: Indolo[6,7-a]pyrrolo[3,4-c]carbazoles
    Engler, TA
    Furness, K
    Malhotra, S
    Sanchez-Martinez, C
    Shih, C
    Xie, W
    Zhu, GX
    Zhou, X
    Conner, S
    Faul, MM
    Sullivan, KA
    Kolis, SP
    Brooks, HB
    Patel, B
    Schultz, RM
    DeHahn, TB
    Kirmani, K
    Spencer, CD
    Watkins, SA
    Considine, EL
    Dempsey, JA
    Ogg, CA
    Stamm, NB
    Anderson, BD
    Campbell, RM
    Vasudevan, V
    Lytle, ML
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (14) : 2261 - 2267
  • [6] Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase
    Heerding, Dirk A.
    Rhodes, Nelson
    Leber, Jack D.
    Clark, Tammy J.
    Keenan, Richard M.
    Lafrance, Louis V.
    Li, Mei
    Safonov, Igor G.
    Takata, Dennis T.
    Venslavsky, Joseph W.
    Yamashita, Dennis S.
    Choudhry, Anthony E.
    Copeland, Robert A.
    Lai, Zhihong
    Schaber, Michael D.
    Tummino, Peter J.
    Strum, Susan L.
    Wood, Edgar R.
    Duckett, Derek R.
    Eberwein, Derek
    Knick, Victoria B.
    Lansing, Timothy J.
    McConnell, Randy T.
    Zhang, ShuYun
    Minthorn, Elisabeth A.
    Concha, Nestor O.
    Warren, Gregory L.
    Kumar, Rakesh
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (18) : 5663 - 5679
  • [7] Signaling by target of rapamycin proteins in cell growth control
    Inoki, K
    Ouyang, H
    Li, Y
    Guan, KL
    [J]. MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS, 2005, 69 (01) : 79 - +
  • [8] Discovery and SAR of spirochromane Akt inhibitors
    Kallan, Nicholas C.
    Spencer, Keith L.
    Blake, James F.
    Xu, Rui
    Heizer, Justin
    Bencsik, Josef R.
    Mitchell, Ian S.
    Gloor, Susan L.
    Martinson, Matthew
    Risom, Tyler
    Gross, Stefan D.
    Morales, Tony H.
    Wu, Wen-I
    Vigers, Guy P. A.
    Brandhuber, Barbara J.
    Skelton, Nicholas J.
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (08) : 2410 - 2414
  • [9] American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy
    Keedy, Vicki Leigh
    Temin, Sarah
    Somerfield, Mark R.
    Beasley, Mary Beth
    Johnson, David H.
    McShane, Lisa M.
    Milton, Daniel T.
    Strawn, John R.
    Wakelee, Heather A.
    Giaccone, Giuseppe
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (15) : 2121 - 2127
  • [10] Base catalyzed Mitsunobu reactions as a tool for the synthesis of aryl sec-alkyl ethers
    Manivel, Pitchai
    Rai, Neithnadka Premsai
    Jayashankara, Vaderapura Puttaramegowda
    Arunachalam, Pirama Nayagam
    [J]. TETRAHEDRON LETTERS, 2007, 48 (15) : 2701 - 2705
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