Ligand Design for Cereblon Based Immunomodulatory Therapy

Important Compound Classes

Title

Ligands to Cereblon (CRBN) and Immunomodulatory Compounds.

Patent Application Number

WO 2020/006264 A1 and WO 2020/006233 A1

Publication Date

January 02, 2020

Priority Application

US 62/692,176 and 62/692,167

Priority Date

June 29, 2018

Inventors

Gray, N.; Zhang, T.; Fischer, E.; Verano, A.; He, Z.; Du, G.; Donovan, K.; Nowak, R.; Yuan, C.; Liu, H.

Assignee Company

Dana-Farber Cancer Institute, Inc., 26 Greenview Avenue, Boston, Massachusetts 02130 (US).

Disease Area

Cancer

Biological Target

Cereblon (CRBN)

Summary

Cereblon (CRBN) is a multifunctional protein located in the cytoplasm, nucleus, and peripheral membrane of the human brain and other tissues. CRBN is highly expressed in the hippocampus of the brain, which is known for its involvement in memory and learning processes. In addition, CRBN plays an essential role in normal metabolic function and normal physiological functions that maintain cell growth and proliferation. It Interacts with other proteins like the DNA damage-binding protein-1 (DDBB1), Cullin 4, and regulator of Cullins 1 to form the functional E3 ubiquitin ligase complex, which targets proteins for degradation or proteolysis through a ubiquitin-proteasome pathway. Interestingly, CRBN has emerged as a particularly high value target for low molecular weight therapeutics that direct protein–protein interactions between the CRL4–CRBN E3 ubiquitin ligase and substrate. CRBN is also involved in the occurrence of many diseases such as cancer.

Cereblon modulators (CM) such as the infamous drug thalidomide were used over-the-counter in various indications including morning sickness but caused thousands of cases of severe birth defects and were withdrawn from the market. However, it later found clinical use in the treatment of leprosy and multiple myeloma. Immunomodulatory drugs (IMiDs) are new class of anticancer drugs that are derived from thalidomide for the treatment of multiple myeloma. In addition, thalidomide analogues like lenalidomide and pomalidomide are approved for the treatment of hematological malignancies. CM bind to cereblon and modify its surface to create a new interface for target substrate binding.

The first CM discovered that activate the cereblon–CRL4 ubiquitin ligase toward specific protein targets were the Ikaros (IKZF1) and Aiolos (IKZF3). The ability to selectively and differentially degrade various substrates is crucial for the CRBN E3 ligase modulators in drug discovery.

Proteolysis TArgeting Chimeras (PROTACs) comprise heterobifunctional degraders with multiple structurally and functionally differentiated components in which one end of the molecule binds to an E3 ligase, the other end binds to an interface of a target protein, and these are connected by a linker that spans the binding pockets and promotes ternary complex formation.

Definitions

R₂ = H, CH₂, etc.;

R₃ = H;

R₄ = heterocycle, C=O, alkyl, etc.

Key Structures

Biological Assay

Lenalidomide displacement assay and cellular CRBN dBET6 displacement assay were used.

Biological Data

The table below shows IC₅₀ and the corresponding K_i values in [μM] for lenalidomide and representative compounds.

Recent Review Articles

• 1.Burslem G. M.; Crews C. M.. Cell 2020, 118, 102.
• 2.Gao H.; Sun X.; Rao Y.. ACS Med. Chem. Lett. 2020, 11, 237.
• 3.Guo J.; Liu J.; Wei W.. Cell Res. 2020, 29, 179.
• 4.Holthof L. C.; Mutis T.. Cancers 2020, 12, 988.
• 5.Piret J.; Boivin G.. Clin. Microbiol. Rev. 2020, 33, 105.
• 6.Gao S.; Song Y.; Wang S.. Biomark. Res. 2020, 8, 2.

The author declares no competing financial interest.