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Mechanism of resistance to bet bromodomain inhibitors

A bromodomain, bromodomain protein technology, applied in the field of the mechanism of resistance to BET bromodomain inhibitors, can solve problems such as lack of understanding

Inactive Publication Date: 2018-06-08
DANA FARBER CANCER INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, adaptive disease resistant to BET inhibitors is a common theme in the general literature on BBI for cancer, yet a mechanistic understanding is still completely lacking

Method used

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  • Mechanism of resistance to bet bromodomain inhibitors
  • Mechanism of resistance to bet bromodomain inhibitors
  • Mechanism of resistance to bet bromodomain inhibitors

Examples

Experimental program
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preparation example Construction

[0308] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparation methods comprise the steps of combining the active ingredients described herein, such as BET inhibitors and / or PP2A activators, with carriers or excipients and / or one or more other auxiliary ingredients, and then, if If necessary and / or desired, the product is formed and / or packaged in the desired single-dose unit or multi-dose units. Pharmaceutical compositions may be prepared, packaged and / or sold in bulk, in single unit dose and / or in multiple unit dose form. As used herein, a "unit dose" is a discrete quantity of a pharmaceutical composition containing a predetermined quantity of an active ingredient. The amount of active ingredient is usually equal to the dose of active ingredient to be administered to the subject, and / or a convenient fraction of such a dose, eg half or a third of such dose.

[0309] The pharmaceutical form...

example

[0324] Sensitivity of breast cancer to BET bromodomain inhibition

[0325] The role of BBI is first in a group reflecting isoforms defined according to transcription (luminal type, HER2 + Evaluated in breast cancer cells of both basal and mesenchymal subpopulations, as well as TNBC types 3,22. In addition to JQ1, samples of chemical probes with different structures (iBET151, PFI-1), the drug under investigation (iBET, GSK-762; Y803, OTX-015) and inactive analogues (alprazolam and the inactive JQ1 enantiomer, R-JQ1). Proliferation of most TNBC cell lines was significantly inhibited in a potency-proportional manner with IC50 in the low nM range, while luminal cell lines were relatively resistant ( Figure 1A ). The dependence of TNBC cells on the BET bromodomain was confirmed by RNA interference, which showed that downregulation of BRD4 consistently phenotypes reverted to BBI ( Figure 1B with Figures 7A to 7B ).

[0326] To understand the role of BBI on TNBC proliferati...

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Abstract

The present disclosure provides combination therapy comprising a BET inhibitor and a protein phosphatase 2A (PP2A) activator, a B-cell lymphoma-2 (Bcl-2) inhibitor, a B-cell lymphoma-extra-large (Bcl-xl) inhibitor, a casein kinase 2 (CK2) inhibitor, and / or a mediator complex subunit 1 (MEDl) for cancer. The combination therapy is expected to be synergistic in treating the cancer, compared to the monotherapy. Methods for identifying a subject having a cancer that is resistant to or at risk of developing resistance to bromodomain and extra terminal (BET) inhibitor therapy are also provided.

Description

[0001] related application [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 203,128, filed August 10, 2015, the contents of which are incorporated herein by reference in their entirety. [0003] governmental support [0004] This patent was made with government support under CA168504 and CA103867 awarded by the National Institutes of Health and CDMRP BC122003 and CA120184 awarded by the US Department of Defense. The government has certain rights in this patent. Background technique [0005] Triple-negative breast cancer (TNBC) is a major breast tumor subtype characterized by lack of expression of estrogen receptor (ER) and progesterone receptor (PR), as well as lack of human epidermal growth factor receptor 2 (HER2 ) amplification. TNBC patients have a poor clinical outcome due to a higher 5-year recurrence risk than any other subtype, especially at more distant sites. Cancer genome sequencing studies focused on TN...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/517C07D239/91
CPCA61K45/06A61K31/137A61K31/5415A61K31/551A61K31/635G01N33/6872G01N2800/52C07D215/42C07D471/04C07D255/04C07D495/14A61P35/00A61P43/00A61K2300/00A61K31/4745A61K31/496A61K39/395G01N33/57415
Inventor K·波利亚克S·舒J·E·布拉德内尔C·Y·林
Owner DANA FARBER CANCER INST INC
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