Dana-farber-cancer Institute Inc.

Hai-Tsang Huang

Nathanael Schiander Gray

Dennis Dobrovolsky

Hwan Geun Choi

Tinghu Zhang

Jean Zhao

Yubao Wang

James Elliott Bradner

Dennis Buckley

Georg Winter

Nathanael S Gray

Li Tan

Mette Ishoey Rosenbaum

The present application provides bifunctional compounds of Formula (X): or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for Bruton's tyrosine kinase (BTK). The present application also relates to methods for the targeted degradation of BTK through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to BTK which can be utilized in the treatment of disorders modulated by BTK.

Degradation of bruton's tyrosine kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligand and methods of use

Degradation of Bruton's tyrosine kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligand and methods of use

The present application provides bifunctional compounds of Formula (I): or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases (e.g., Bcr-Abl). The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.

Degradation of protein kinases by conjugation of protein kinase inhibitors with E3 ligase ligand and methods of use

Provided herein are small molecule inhibitors of maternal embryonic leucine zipper kinase (MELK) having the structure of formula (I), wherein X and R-Rare defined in the specification. The compounds are useful for treating cancer and other conditions or diseases associated with aberrant MELK expression. Also provided herein are pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The invention also provides methods of treating cancers associated with over-expression of MELK.

Salicylate inhibitors of MELK and methods of use

The present application provides bifunctional compounds of Formula (I): or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for Bruton's tyrosine kinase (BTK). The present application also relates to methods for the targeted degradation of BTK through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to BTK which can be utilized in the treatment of disorders modulated by BTK.

Provided herein are tricyclic small molecule inhibitors of maternal embryonic leucine zipper kinase (MELK). The compounds are useful for treating cancer and other conditions or diseases associated with aberrant MELK expression. Also provided herein are pharmaceutical compositions comprising a tricyclic compound of the invention and a pharmaceutically acceptable carrier. The invention also provides methods of treating cancers associated with over-expression of MELK.

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Boston, MA, United States of America

Hai-Tsang Huang