Dana-Farber-Cancer Institute Inc.

Everdisplay Optronics (Shanghai) Limited

Li Tan

Nathanael Schiander Gray

Guang Yang

Sara Jean Buhrlage

Steven P Treon

Hwan Geun Choi

James Elliott Bradner

Dennis Buckley

Georg Winter

Hai-Tsang Huang

Mette Ishoey Rosenbaum

ChihMing Lin

HsinAn Lin

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

The invention relates to compounds and their use in the treatment of disease. Novel irreversible inhibitors of wild-type and mutant forms of EGFR, FGFR, ALK, ROS, JAK, BTK, BLK, ITK, TEC, and/or TXK and their use for the treatment of cell proliferation disorders are described.

Kinase inhibitors for the treatment of disease

The present invention provides compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A-18)), and methods for treating Waldenstr&#xf6;m's macroglobulinemia (WM) and other B cell neoplams in a subject using the compounds. The methods comprise administering to a subject in need thereof an effective amount of the compounds. Also provided are methods to treat B cell neoplasms using the compounds in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. 

Methods to treat lymphoplasmacytic lymphoma

The present invention provides compounds of any one of Formulae (I) to (V) (e.g., compounds of any one of Formulae (I-1) to (I-9)), and methods for treating Waldenstr&#xf6;m's macroglobulinemia (WM) and other B cell neoplams in a subject using the compounds. The methods comprise administering to a subject in need thereof an effective amount of the compounds. Also provided are methods to treat B cell neoplasms using the compounds in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. 

Methods of treatment of conditions or diseases associated with myeloid differentiation primary response (MYD88) protein using a selective HCK inhibitor are provided herein.

HCK as a therapeutic target in MYD88 mutated diseases

The present invention provides kinase inhibitors, such as compounds of Formula (I) and Formula (II). The compounds may covalently or non-covalently bind a kinase (e.g., Janus kinase 3 (JAK3)). Also provided are pharmaceutical compositions, kits, methods, and uses that involve the compounds for reducing the activity of a kinase and/or treating and/or preventing a condition associated with aberrant activity of a kinase (e.g., a proliferative disease, inflammatory disorder, autoimmune disorder, painful condition, and/or viral infection). (I) (II) 

Janus kinase inhibitors and uses thereof

The present invention provides Janus kinase inhibitors, such as compounds of Formula (I) and Formula (II) wherein Rand Rcomprise a tagged hydrophobic moiety R. The compounds may covalently or non-covalently bind a kinase (e.g., Janus kinase 3 (JAK3)). The hydrophobic moiety Rmay signal to the intracellular protein homeostasis machinery to induce degradation of the targeted kinase. Also provided are pharmaceutical compositions, kits, methods, and uses that involve the compounds for reducing the activity of a kinase and/or treating and/or preventing a condition associated with aberrant activity of a kinase (e.g., a proliferative disease, inflammatory disorder, autoimmune disorder, painful condition, and/or viral infection). 

Hydrophobically tagged janus kinase inhibitors and uses thereof

The present invention provides compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A-18)), and methods for treating Waldenstr&#xf6;m's macroglobulinemia (WM) and other B cell neoplasm in a subject using the compounds. The methods comprise administering to a subject in need thereof an effective amount of the compounds. Also provided are methods to treat B cell neoplasms using the compounds in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. 

The present disclosure discloses a method of manufacturing the LTPS array substrate, comprising: depositing a polysilicon layer and an amorphous silicon layer on the substrate successively and crystallizing the amorphous silicon layer to form the polysilicon layer by laser annealing; coating a photoresist layer covering the PMOS area, NMOS area and TFT area of the polysilicon layer; forming a polysilicon pattern and a channel by dry etching the polysilicon layer, then removing the regions of the photoresist layer which are thinner and covering the NMOS area and the TFT area by ashing, the region of the photoresist layer covering the PMOS area is remained. The present disclosure saves the cost of the equipment, improves the yield, reduces the design defect and the process difficulty of the conventional process using 8 photomasks.

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Boston, MA, United States of America

Li Tan