Third generation quinoline-3-carboxamide transcriptional disrupter of HDAC4, HIF-1α, and MEF-2 signaling for metastatic castration-resistant prostate cancer.
HDAC4
aryl hydrocarbon receptor
drug development
prostate cancer
tasquinimod
Journal
The Prostate
ISSN: 1097-0045
Titre abrégé: Prostate
Pays: United States
ID NLM: 8101368
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
15
06
2023
received:
07
03
2023
accepted:
18
07
2023
pmc-release:
01
11
2024
medline:
19
9
2023
pubmed:
10
8
2023
entrez:
10
8
2023
Statut:
ppublish
Résumé
The quinoline-3-carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration-resistant prostate cancer(mCRPC), TasQ (1 mg/day) increased time-to-progression, but not overall survival. TasQ analogs were chemically synthesized and tested for activity compared to the parental compound. These included HDAC4 enzymatic assays, qRT-PCR and western blot analyses of gene and protein expression following treatment, in vitro and in vivo efficacy against multiple prostate cancer models including PDXs, pharmacokinetic analyses,AHR binding and agonist assays, SPR analyses of binding to HDAC4 and NCoR1, RNAseq analysis of in vivo tumors, 3D endothelial sprouting assays, and a targeted kinase screen. Genetic knockout or knockdown controls were used when appropriate. Here, we document that, on this regimen (1 mg/day), TasQ blood levels are 10-fold lower than the optimal concentration (≥2 μM) needed for anticancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that TasQ is an arylhydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 μM to produce unwanted off-target side effects. Therefore, we screened a library of TasQ analogsto maximize on-target versus off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and 5-fold greater potency against prostate cancer patient-derived xenografts. This increased therapeuticindex nominates ESATA-20 as a lead candidate forclinical development as an orally active third generation quinoline-3-carboxamide analog thatretains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.
Sections du résumé
BACKGROUND
The quinoline-3-carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration-resistant prostate cancer(mCRPC), TasQ (1 mg/day) increased time-to-progression, but not overall survival.
METHODS
TasQ analogs were chemically synthesized and tested for activity compared to the parental compound. These included HDAC4 enzymatic assays, qRT-PCR and western blot analyses of gene and protein expression following treatment, in vitro and in vivo efficacy against multiple prostate cancer models including PDXs, pharmacokinetic analyses,AHR binding and agonist assays, SPR analyses of binding to HDAC4 and NCoR1, RNAseq analysis of in vivo tumors, 3D endothelial sprouting assays, and a targeted kinase screen. Genetic knockout or knockdown controls were used when appropriate.
RESULTS
Here, we document that, on this regimen (1 mg/day), TasQ blood levels are 10-fold lower than the optimal concentration (≥2 μM) needed for anticancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that TasQ is an arylhydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 μM to produce unwanted off-target side effects. Therefore, we screened a library of TasQ analogsto maximize on-target versus off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and 5-fold greater potency against prostate cancer patient-derived xenografts.
CONCLUSION
This increased therapeuticindex nominates ESATA-20 as a lead candidate forclinical development as an orally active third generation quinoline-3-carboxamide analog thatretains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.
Identifiants
pubmed: 37559436
doi: 10.1002/pros.24606
pmc: PMC10559933
mid: NIHMS1925341
doi:
Substances chimiques
quinoline-3-carboxamide
0
HDAC4 protein, human
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Repressor Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1470-1493Subventions
Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States
Informations de copyright
© 2023 Wiley Periodicals LLC.
Références
Mol Pharmacol. 2009 Jun;75(6):1412-20
pubmed: 19299563
Fish Physiol Biochem. 2015 Feb;41(1):289-98
pubmed: 25186110
Cancer Res. 2013 Feb 15;73(4):1386-99
pubmed: 23149916
Br J Cancer. 2009 Oct 20;101(8):1233-40
pubmed: 19755981
J Neuroimmunol. 2016 Sep 15;298:9-15
pubmed: 27609269
PLoS One. 2014 Jul 02;9(7):e101521
pubmed: 24988463
J Med Chem. 2004 Apr 8;47(8):2075-88
pubmed: 15056005
J Biol Chem. 2008 Sep 26;283(39):26694-704
pubmed: 18614528
Biochem Pharmacol. 2007 Aug 1;74(3):465-76
pubmed: 17559812
Prostate. 1995 May;26(5):235-46
pubmed: 7538663
Mol Pharmacol. 2004 May;65(5):1225-37
pubmed: 15102951
Clin Cancer Res. 2013 Dec 15;19(24):6891-901
pubmed: 24255071
J Org Chem. 2015 Jun 5;80(11):5912-8
pubmed: 25938581
Prostate. 2012 Jun 1;72(8):913-24
pubmed: 22287276
Cancer Res. 1995 Apr 1;55(7):1499-504
pubmed: 7533663
Prostate. 2017 Mar;77(4):385-395
pubmed: 27862097
Mol Cancer. 2010 May 17;9:107
pubmed: 20470445
Cancer Res. 1997 Aug 15;57(16):3325-30
pubmed: 9269988
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17910-5
pubmed: 19805192
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19579-86
pubmed: 19020076
Ann Oncol. 2017 Nov 01;28(11):2741-2746
pubmed: 29059273
Mol Cell Biol. 2013 Nov;33(22):4473-91
pubmed: 24043307
J Natl Cancer Inst. 1998 Nov 4;90(21):1648-53
pubmed: 9811314
Prostate. 2007 May 15;67(7):790-7
pubmed: 17373719
Bioorg Med Chem Lett. 2001 Feb 26;11(4):451-2
pubmed: 11229745
Toxicol Appl Pharmacol. 2017 Jul 1;326:54-65
pubmed: 28433708
Mol Med Rep. 2017 Jul;16(1):174-180
pubmed: 28498411
Oncotarget. 2016 Nov 1;7(44):71298-71308
pubmed: 27542256
Oncotarget. 2014 Sep 30;5(18):8093-106
pubmed: 25193858
Biochim Biophys Acta Rev Cancer. 2018 Aug;1870(1):15-22
pubmed: 30006019
Nucleic Acids Res. 2018 Dec 14;46(22):11776-11788
pubmed: 30321390
Cancer Detect Prev. 2004;28(2):88-93
pubmed: 15068831
Mult Scler. 2000 Apr;6(2):99-104
pubmed: 10773855
Cancer Res. 1996 Aug 1;56(15):3404-8
pubmed: 8758902
J Biol Chem. 1999 Oct 1;274(40):28708-15
pubmed: 10497241
Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6145-E6152
pubmed: 27671624
Microvasc Res. 2003 Sep;66(2):102-12
pubmed: 12935768
FEBS Lett. 2009 Jan 5;583(1):55-60
pubmed: 19071119
J Biol Chem. 2011 Nov 4;286(44):38095-38102
pubmed: 21917920
Cancer Res. 2005 Dec 15;65(24):11565-71
pubmed: 16357166
JCI Insight. 2021 Apr 22;6(8):
pubmed: 33724955
J Mol Biol. 2005 Jan 7;345(1):91-102
pubmed: 15567413
J Clin Oncol. 2011 Oct 20;29(30):4022-8
pubmed: 21931019
J Biol Chem. 1996 Jul 26;271(30):17771-8
pubmed: 8663540
Expert Opin Investig Drugs. 2010 Oct;19(10):1235-43
pubmed: 20836618
PLoS One. 2012;7(3):e34207
pubmed: 22470535
Mol Cell Biol. 2008 May;28(10):3437-45
pubmed: 18332106
Oncogene. 2007 Aug 13;26(37):5450-67
pubmed: 17694086
Cancer Immunol Res. 2015 Feb;3(2):136-48
pubmed: 25370534
Medicine (Baltimore). 2018 Nov;97(46):e13204
pubmed: 30431595
Cancer Res. 2006 Sep 1;66(17):8814-21
pubmed: 16951198
Oncotarget. 2019 Dec 03;10(64):6845-6854
pubmed: 31839878
J Clin Oncol. 2016 Aug 1;34(22):2636-43
pubmed: 27298414
Oncogene. 2020 Nov;39(45):6935-6949
pubmed: 32989253
Oxid Med Cell Longev. 2017;2017:5213186
pubmed: 29098061
Prostate. 2006 Dec 1;66(16):1768-78
pubmed: 16955399
Prostate. 2012 May 1;72(6):638-48
pubmed: 21837778
Nat Rev Cancer. 2008 Sep;8(9):705-13
pubmed: 19143055
Cancer Res. 1992 Jun 1;52(11):3022-8
pubmed: 1591718
Trends Biochem Sci. 2002 Jan;27(1):40-7
pubmed: 11796223
Cancer Res. 1993 Apr 15;53(8):1833-7
pubmed: 7682157
Biochim Biophys Acta. 2002 Oct 11;1578(1-3):73-83
pubmed: 12393189