Cereblon ligands and bifunctional compounds comprising the same

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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present disclosure claims priority to U.S. Provisional Application No. 62 / 452,972, filed 31 Jan. 2017, which is incorporated herein by reference in its entirety.INCORPORATION BY REFERENCE[0002]U.S. patent application Ser. No. 15 / 230,354, filed on Aug. 5, 2016, published as U.S. Patent Application Publication No. 2017 / 0065719; and U.S. patent application Ser. No. 15 / 801,243, filed on 1 Nov. 2017; and U.S. patent application Ser. No. 15 / 206,497 filed 11 Jul. 2016; and U.S. patent application Ser. No. 15 / 209,648 filed 13 Jul. 2016; and U.S. patent application Ser. No. 15 / 730,728, filed on Oct. 11, 2017; U.S. patent application Ser. No. 15 / 829,541, filed on Dec. 1, 2017; U.S. patent application Ser. No. 15 / 881,318, filed on Jan. 26, 2018; and U.S. patent application Ser. No. 14 / 686,640, filed on Apr. 14, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. patent application Ser. No. 14 / 792,414, filed on Jul. ...

AI Technical Summary

Benefits of technology

[0013]The present disclosure describes bifunctional compounds which function to recruit endogenous proteins to an E3 Ubiquitin Ligase for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation / inhibition of targeted polypeptides from virtually any protein class or family. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., multiple myeloma.

Problems solved by technology

On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved.

The development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions.

Thus, despite the rapid progress of BRD4 inhibitors, the effect of BRD4 inhibition has been encouraging, but less than ideal, as the effect is mostly cytostatic and requires relatively high concentration of inhibitors.

However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents.

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