Small molecule regulators of steroid receptor coactivators and methods of use thereof

An unsubstituted, compound technology applied in the field of small molecule modulators of steroid receptor coactivators and their use

Pending Publication Date: 2019-02-05
BAYLOR COLLEGE OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although breast cancer cells can become resistant to endocrine therapy, these cancer cells must recruit coactivators to survive

Method used

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  • Small molecule regulators of steroid receptor coactivators and methods of use thereof
  • Small molecule regulators of steroid receptor coactivators and methods of use thereof
  • Small molecule regulators of steroid receptor coactivators and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0386] Embodiment 1: the synthesis of compound

[0387] All chemicals were purchased from Sigma-Aldrich (Milwaukee, WI) or Alfa Aesar (Ward Hill, MA) unless otherwise noted. All other solvents and reagents were used as obtained without further purification. By Varian 400-MR spectrometer (Palo Alto, CA) on 1 H-NMR to characterize the compound. Chemical shifts (δ) are referenced to solvent signals [ 1 H NMR: DMSO-d6(2.50)] are given in ppm. UV-Vis measurements were performed in 10 × 10 mm quartz cuvettes using a Cary 60 UV-Vis spectrometer. Flash chromatography was performed on a Teledyne ISCO CombiFlash Rf200. ESI mass spectra were measured on an Agilent mass spectrometer (6130 single quadrupole).

[0388] Compounds as described herein are prepared according to the methods described below. In some cases, the synthesized compounds existed as mixtures of tautomers.

[0389] Synthesis of compound SI-3:

[0390]

[0391] To a solution of 2-chloro-lH-benzo[d]imidazole (9...

Embodiment 2

[0429] Example 2: Small Molecule Modulators of Steroid Receptor Coactivators

[0430] Described herein is a new class of small molecule modulators (ie, inhibitors and stimulators) of steroid receptor coactivators that are useful in the treatment of neurological and metabolic disorders, inflammatory diseases, and cancer.

[0431] SI compounds are effective in cancer cell lines

[0432] The compounds described herein were synthesized as described in Example 1. ICs were measured in MDA-MB-468, BT-474 and MCF-7 cells by incubating a range of concentrations of the corresponding compounds for 72 hours 50 value. The results are shown in Table 1.

[0433] Table 1

[0434] compound

MDA-MB-468

BT-474

MCF-7

SI-3

NA*

SI-4

NA*

SI-5

NA*

SI-6

++

SI-7

NA*

SI-8

NA*

SI-9

+++

SI-10

+++

+++

SI-11

+++

+++

...

Embodiment 3

[0443] SI-12 was tested in pancreatic, lung, brain and melanoma cancers. Representative examples of pancreatic tumor treatment are described below. Panc-1 cells stably expressing firefly luciferase (Panc-1-Luc, 0.5×10 6 cells / mouse) into the tail of the pancreas of SCID mice (6-7 weeks). Mice were randomly divided into two groups (n=8 / group) based on luciferase imaging. Eight days after tumor inoculation, both groups were administered SI-12 (10 mg / kg, ip injection, once daily) or an equal volume of vehicle control five times a week. Tumor growth and systemic toxicity were monitored based on luciferase imaging and weekly body weight. Mice were sacrificed after 8 weeks of treatment. SI-12 treatment significantly delayed pancreatic tumor growth ( image 3 A and 3C), while causing minimal weight loss ( image 3 B). At the end of the experiment, tumors were harvested and weighed. The average tumor weight in SI-12-treated mice was approximately 30% that of the vehicle-treate...

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Abstract

Small molecule regulators of steroid receptor coactivator (SRC) family proteins are provided, as well as methods for their use in treating or preventing SRC-related diseases. The SRC-related diseasescan include cancer, metabolic disorders, human immunodeficiency virus, neurodegenerative disorders, and / or inflammatory diseases. Also provided are methods for regulating SRC family proteins in a cell.

Description

[0001] Cross Reference to Priority Application [0002] This application claims priority to U.S. Provisional Application No. 62 / 320,121, filed April 8, 2016, and U.S. Provisional Application No. 62 / 441,658, filed January 3, 2017, the entire contents of which are incorporated herein by reference. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with Government support under Grant Numbers R01GM115622, HD076596, DK059820, and R01CA112403 awarded by the National Institutes of Health and DOD BC120894 awarded by the Department of Defense. The government has certain rights in this invention. Background technique [0005] Coactivators are non-DNA binding proteins that mediate the transcriptional activity of nuclear receptors (NRs) and many other transcription factors. More than 400 coactivators have been identified and are associated with a wide variety of human diseases, including neurological and metabolic disorders, inflammatory diseases and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D401/14C07D401/12C07D405/12C07D409/12C07D413/12C07D417/12C07D471/04C07D487/04C07D498/04A61K31/4402A61P35/00A61K31/506A61K31/4188
CPCC07D403/12C07D401/14C07D401/12C07D405/12C07D409/12C07D413/12C07D417/12C07D471/04C07D487/04C07D498/04A61K31/4184A61K31/426A61K31/4402A61K31/506A61P25/28A61P29/00A61P3/00A61P31/18A61P35/00A61P43/00A61K31/422A61K31/427A61K31/4439A61P25/00C07D513/04
Inventor B.W.奥马利D.M.罗纳德J.王J.徐J.陈
Owner BAYLOR COLLEGE OF MEDICINE
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