Compositions and methods for inducing conformational changes in cereblon and other e3 ubiquitin ligases

Patent metadata

Field	Value
Publication number	US-2021000813-A1
Application number	US-202016852360-A
Country	US
Kind code	A1
Filing date	Apr 17, 2020
Priority date	Jun 27, 2014
Publication date	Jan 7, 2021
Grant date	—

Abstract

Provided herein are compositions, therapeutic methods, screening methods, computational methods and biomarkers based upon the elucidation of the interaction among cereblon, its substrates and certain compounds or agents, including small molecules, peptides, and proteins.

First claim

1 - 73 . (canceled)

74 . A method of identifying a test compound that induces a cereblon (CRBN) conformational change or an alteration of properties of a CRBN surface, wherein the method comprises:
(a) obtaining a first three-dimensional structure of CRBN and a reference compound; (b) obtaining a second three-dimensional structure of CRBN and the test compound; and (c) comparing the first three-dimensional structure with the second three-dimensional structure;
wherein a difference in the first and second three-dimensional structures is indicative of a test compound that induces the CRBN conformational change or alteration of properties of a CRBN surface;
wherein the CRBN conformational change or the alteration of properties of the CRBN surface occurs in a cereblon modifying agent (CMA) binding pocket of the CRBN, or within an adjacent region thereof; and
wherein the three-dimensional structure is assessed using x-ray crystallography, NMR spectroscopy, dual polarization interferometry, vibrational spectroscopy, or cryo-electron microscopy.

75 . The method of claim 74 , wherein the test compound has a specific downstream biological activity and wherein the difference in the first and second three-dimensional structures is indicative of the test compound having the specific downstream biological activity.

76 . The method of claim 75 , wherein the method further comprises assaying the specific downstream biological activity.

77 . The method of claim 75 , wherein the method further comprises administering the test compound to a patient, wherein the specific downstream biological activity is modulated in the patient, and wherein optionally the patient has a disease, and one or more symptoms of the disease are alleviated following administration of the test compound.

78 . The method of claim 74 , wherein the test compound has a specific therapeutic efficacy and wherein the difference in the first and second three-dimensional structures is indicative of the test compound having the specific therapeutic efficacy.

79 . The method of claim 78 , wherein the method further comprises administering the test compound to a patient having a disease, wherein one or more symptoms of the disease are alleviated following administration of the test compound.

80 . The method of claim 78 , wherein the method further comprises administering the test compound to a patient having a disease, disorder or condition, wherein one or more symptoms of the disease, disorder or condition are alleviated following administration of the test compound.

81 . The method of claim 74 , wherein the conformational change or alteration has an effect on W380, W386 and/or W400 of CRBN; has an effect on E377 of CRBN; or has an effect on V388 of CRBN; wherein the CRBN is human CRBN.

82 . The method of claim 74 , wherein the CRBN is further bound to DDB1, Cul4, Roc1, or any combination thereof.

83 . The method of claim 74 , wherein the CRBN is further bound to DDB1.

84 . The method of claim 74 , wherein the CRBN conformational change or the alteration of properties of the CRBN surface is assessed by x-ray crystallography.

85 . The method of claim 74 , wherein the CRBN is human CRBN or murine CRBN.

Assignees

• Celgene Corp

Inventors

• Chamberlain Philip
• Cathers Brian E
• Lopez-Girona Antonia

Classifications

• G16B15/30

  Drug targeting using structural data; Docking or binding prediction · CPC title

• A61K31/454 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title