Literature DB >> 26372073

Reengineered tricyclic anti-cancer agents.

David B Kastrinsky1, Jaya Sangodkar2, Nilesh Zaware1, Sudeh Izadmehr2, Neil S Dhawan2, Goutham Narla3, Michael Ohlmeyer4.   

Abstract

The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP, CPZ, CIP) by replacing the basic amine with a neutral polar functional group (e.g., RTC-1, RTC-2) abrogated their CNS effects as demonstrated by in vitro pharmacological assays and in vivo behavioral models. Further optimization generated several phenothiazines and dibenzazepines with improved anti-cancer potency, exemplified by RTC-5. This new lead demonstrated efficacy against a xenograft model of an EGFR driven cancer without the neurotropic effects exhibited by the parent molecules. Its effects were attributed to concomitant negative regulation of PI3K-AKT and RAS-ERK signaling.
Copyright © 2015 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Clomipramine; Dibenzazepine; Neuroleptic; Phenothiazine; Tricyclic

Mesh：

Substances：

Year:  2015        PMID： 26372073     DOI： 10.1016/j.bmc.2015.07.007

Source DB:  PubMed          Journal:  Bioorg Med Chem        ISSN： 0968-0896            Impact factor:   3.641


  22 in total

Review 1.  Targeting PP2A in cancer: Combination therapies.

Authors:  Sahar Mazhar; Sarah E Taylor; Jaya Sangodkar; Goutham Narla
Journal:  Biochim Biophys Acta Mol Cell Res       Date:  2018-09-01       Impact factor: 4.739

2.  Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth.

Authors:  Jaya Sangodkar; Abbey Perl; Rita Tohme; Janna Kiselar; David B Kastrinsky; Nilesh Zaware; Sudeh Izadmehr; Sahar Mazhar; Danica D Wiredja; Caitlin M O'Connor; Divya Hoon; Neil S Dhawan; Daniela Schlatzer; Shen Yao; Daniel Leonard; Alain C Borczuk; Giridharan Gokulrangan; Lifu Wang; Elena Svenson; Caroline C Farrington; Eric Yuan; Rita A Avelar; Agnes Stachnik; Blake Smith; Vickram Gidwani; Heather M Giannini; Daniel McQuaid; Kimberly McClinch; Zhizhi Wang; Alice C Levine; Rosalie C Sears; Edward Y Chen; Qiaonan Duan; Manish Datt; Shozeb Haider; Avi Ma'ayan; Analisa DiFeo; Neelesh Sharma; Matthew D Galsky; David L Brautigan; Yiannis A Ioannou; Wenqing Xu; Mark R Chance; Michael Ohlmeyer; Goutham Narla
Journal:  J Clin Invest       Date:  2017-05-15       Impact factor: 14.808

3.  Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer.

Authors:  Kimberly McClinch; Rita A Avelar; David Callejas; Sudeh Izadmehr; Danica Wiredja; Abbey Perl; Jaya Sangodkar; David B Kastrinsky; Daniela Schlatzer; Maxwell Cooper; Janna Kiselar; Agnes Stachnik; Shen Yao; Divya Hoon; Daniel McQuaid; Nilesh Zaware; Yixuan Gong; David L Brautigan; Stephen R Plymate; Cynthia C T Sprenger; William K Oh; Alice C Levine; Alexander Kirschenbaum; John P Sfakianos; Rosalie Sears; Analisa DiFeo; Yiannis Ioannou; Michael Ohlmeyer; Goutham Narla; Matthew D Galsky
Journal:  Cancer Res       Date:  2018-01-22       Impact factor: 12.701

4.  RABL6A inhibits tumor-suppressive PP2A/AKT signaling to drive pancreatic neuroendocrine tumor growth.

Authors:  Shaikamjad Umesalma; Courtney A Kaemmer; Jordan L Kohlmeyer; Blake Letney; Angela M Schab; Jacqueline A Reilly; Ryan M Sheehy; Jussara Hagen; Nitija Tiwari; Fenghuang Zhan; Mariah R Leidinger; Thomas M O'Dorisio; Joseph Dillon; Ronald A Merrill; David K Meyerholz; Abbey L Perl; Bart J Brown; Terry A Braun; Aaron T Scott; Timothy Ginader; Agshin F Taghiyev; Gideon K Zamba; James R Howe; Stefan Strack; Andrew M Bellizzi; Goutham Narla; Benjamin W Darbro; Frederick W Quelle; Dawn E Quelle
Journal:  J Clin Invest       Date:  2019-03-04       Impact factor: 14.808

5.  Direct activation of PP2A for the treatment of tyrosine kinase inhibitor-resistant lung adenocarcinoma.

Authors:  Rita Tohmé; Sudeh Izadmehr; Sai Gandhe; Giancarlo Tabaro; Sanjay Vallabhaneni; Ava Thomas; Neal Vasireddi; Neil S Dhawan; Avi Ma'ayan; Neelesh Sharma; Matthew D Galsky; Michael Ohlmeyer; Jaya Sangodkar; Goutham Narla
Journal:  JCI Insight       Date:  2019-02-21

6.  Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A.

Authors:  Jean-Baptiste Garsi; Vito Vece; Lorenzo Sernissi; Catherine Auger-Morin; Stephen Hanessian; Alison N McCracken; Elizabeth Selwan; Cuauhtemoc Ramirez; Amogha Dahal; Nadine Ben Romdhane; Brendan T Finicle; Aimee L Edinger
Journal:  Bioorg Med Chem Lett       Date:  2019-07-19       Impact factor: 2.823

Review 7.  Therapeutic targeting of PP2A.

Authors:  Caitlin M O'Connor; Abbey Perl; Daniel Leonard; Jaya Sangodkar; Goutham Narla
Journal:  Int J Biochem Cell Biol       Date:  2017-10-26       Impact factor: 5.085

8.  Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells.

Authors:  Garry L Coles; Sandra Cristea; James T Webber; Rebecca S Levin; Steven M Moss; Andy He; Jaya Sangodkar; Yeonjoo C Hwang; Julia Arand; Alexandros P Drainas; Nancie A Mooney; Janos Demeter; Jessica N Spradlin; Brandon Mauch; Vicky Le; Yan Ting Shue; Julie H Ko; Myung Chang Lee; Christina Kong; Daniel K Nomura; Michael Ohlmeyer; Danielle L Swaney; Nevan J Krogan; Peter K Jackson; Goutham Narla; John D Gordan; Kevan M Shokat; Julien Sage
Journal:  Cancer Cell       Date:  2020-06-11       Impact factor: 31.743

9.  Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers.

Authors:  Caroline C Farrington; Eric Yuan; Sahar Mazhar; Sudeh Izadmehr; Lauren Hurst; Brittany L Allen-Petersen; Mahnaz Janghorban; Eric Chung; Grace Wolczanski; Matthew Galsky; Rosalie Sears; Jaya Sangodkar; Goutham Narla
Journal:  J Biol Chem       Date:  2019-12-10       Impact factor: 5.157

10.  Phosphoproteomics Profiling of Nonsmall Cell Lung Cancer Cells Treated with a Novel Phosphatase Activator.

Authors:  Danica D Wiredja; Marzieh Ayati; Sahar Mazhar; Jaya Sangodkar; Sean Maxwell; Daniela Schlatzer; Goutham Narla; Mehmet Koyutürk; Mark R Chance
Journal:  Proteomics       Date:  2017-10-25       Impact factor: 3.984
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