Cereblon ligands and bifunctional compounds comprising the same
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A technology of bifunctional compounds and compounds, applied in the fields of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc.
Pending Publication Date: 2021-01-22
ARVINAS OPERATIONS INC
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However, non-specific effects and inability to fully target and regulate certain classes of proteins such as transcription factors remain obstacles to the development of effective anticancer agents
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[1890] A. Protein Degradation Bioassay:
[1891] The following bioassays use representative compounds disclosed herein to assess the levels of protein degradation observed in various cell types.
[1892] In each bioassay, cells are treated with varying amounts of a compound encompassed by the present disclosure. Degradation of the following proteins can be assessed: estrogen receptor alpha (ERα), bromodomain-containing protein 4 (BRD4), androgen receptor (AR) and BRaf proteins.
[1893] 1. ERE Luciferase Assay for Compounds in Table 5
[1894] T47D-KBluc cells ( #CRL_2865, T47D human breast cancer cells stably transfected by estrogen response element / promoter / luciferase reporter gene) were seeded into 96 wells in RPMI growth medium supplemented with 10% fetal bovine serum (FBS) white opaque plates and allowed to adhere overnight in a humidified incubator at 37°C. The next day, cells were treated with PROTACs in a 12-point concentration curve (highest final concentration...
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Abstract
The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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[0001] Cross References to Related Applications [0002] This disclosure is an international application claiming priority to U.S. nonprovisional application No. 15 / 953108, filed April 13, 2018, which is claiming U.S. provisional application No. 1, filed April 14, 2014. 61 / 979,351 is a continuation-in-part of U.S. nonprovisional application filed April 14, 2015 and is claiming U.S. provisional application 61 / 979,351 filed April 14, 2014 and filed on June 14, 2015 Continuation-in-Part of U.S. Nonprovisional Application No. 14 / 792,414, filed July 6, 2015, which is the priority of U.S. Provisional Application No. 62 / 171,090, filed July 4, 2015, all of which are hereby incorporated by reference in their entirety middle. [0003] incorporated by reference [0004] U.S. Patent Application Serial No. 15 / 230,354, filed August 5, 2016, published as U.S. Patent Application Publication No. 2017 / 0065719; and U.S. Patent Application Serial No. 15 / 801,243, filed November 1, 2017; and U....
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