Wisconsin Alumni Research Foundation

Harvard College

Dana-Farber-Cancer Institute Inc.

Massachusetts Institute of Technology

The General Hospital Corporation

Weiping Tang

Stuart L Schreiber

Ka Yang

James Bradner

Gabrielle N Winston-McPherson

Hao Wu

Xiaoxun Li

Douglas A Melton

Shuibing C Chen

Malgorzata Borowiak

Julia Lamenzo Fox

Rene Maehr

Dongxu Shu

Ralph Mazitschek

Stephen J Haggarty

Li-Huei Tsai

Alan D Attie

John M Denu

Mark Patrick Keller

Jill M Kolesar

Wei Xu

Andre Fischer

Haibo Xie

Zhongrui Zhang

Jitian Liu

James Elliot Bradner

Histone deacetylase ('HDAC')-selective inhibitors covalently bonded to a linker covalently bonded to an E3 ubiquitin ligase ligand, and salts thereof; pharmaceutical compositions containing them; methods of using the composition to inhibit neoplastic cell growth in mammals, including humans.

Synthesis of small molecule histone deacetylase 6 degraders, compounds formed thereby, and pharmaceutical compositions containing them

The present disclosure provides compounds according to Formula I and pharmaceutically acceptable salts thereof, as well as compositions including such compounds and a pharmaceutically acceptable carrier or excipient. Further provided are methods of inactivating SIRT6 with compounds of Formula I as well as compounds of Formula III, W—R—Y—R, as described herein. In addition, the present technology provides methods of treatment using such compounds to lower LDL levels, lower triglyceride levels, and/or increase glucose tolerance in a subject, and/or to inhibit proliferation of ovarian, colorectal, hepatocellular, non-small cell lung, glioblastoma, osteosarcoma, pancreatic, and skin cancer cells, and/or inhibit liver and/or kidney fibrosis, and/or promote corneal epithelial wound healing.

Sirtuin 6 protein deacylase (SIRT6) activators

Described are benzoimidazole indolyl methane compounds, pharmaceutical compositions containing them, and use of the compounds to inhibit PCSK9-mediated ailments. The compounds have the structure: 

Benzoimidazole indolyl methanes and methods of using them to inhibit PCKS9 and PCKS9-mediated ailments

Described is a method to make diindolylmethanes and indolyl/pyrrolylmethanes, The method includes the steps of contacting an ether comprising an arylpropargyl moiety and an amine-protected, substituted or unsubstituted aniline moiety with a substituted or unsubstituted indol or a substituted or unsubstituted pyrrole, in the presence of a metal-containing catalyst, for a time and at a temperature to cause an annulation/arylation cascade reaction that yields a diindolylmethane or a indolyl/pyrrolylmethane. The resulting compounds are effective to modulate activity of arylhydrocarbon receptors, to inhibit activity of PCSK9, and to stimulate secretion of glucagon-like peptide 1 in mammals.

Synthesis of diindolylmethanes and indolo[3,2-b]carbazoles, compounds formed thereby, and pharmaceutical compositions containing them

Disclosed are unnatural analogs of Diptoindonesin G, methods to make the analogs, pharmaceutical compositions containing the analogs, and methods of using the analogs to inhibit neoplastic cell growth.

Synthesis of novel analogs of diptoindonesin G, compounds formed thereby, and pharmaceutical compositions containing them

Methods of making indole analogs using a rhodium-containing catalyst are described, along with methods of using the compounds to treat hyperglycemic, hyperlipidemic, or autoimmune disorders in mammals, and corresponding pharmaceutical compositions. Disclosed herein is a method of making indoles. The method comprises contacting a reactant of formula I wherein E is a protecting group, &#x2014;SO2-Aryl, or &#x2014;SO2-substituted-Aryl; and R and R2 are independently selected from the group consisting of hydrogen, halo, C1-C12-alkyl and aryl; with a rhodium(1)-containing catalyst.

Synthesis of cyclopropyl indoles and cyclohepta[B]indoles, pharmaceutical compositions containing them and method of using them

The present invention provides novel compounds of formula (I) and pharmaceutical compositions thereof. The inventive compounds are useful as deacetylase inhibitors (e.g., histone deacetylase inhibitors) and may be useful in the treatment of proliferative diseases such as cancer. In particular, the inventive compounds are HDAC6 inhibitors. The invention also provide synthetic methods for preparing the inventive compounds. 

Deacetylase inhibitors and uses thereof

Certain embodiments disclosed herein are directed to a method of producing endoderm cells, such as definitive endoderm cells by exposing stem cells such as embryonic stem cells or induced pluripotent stem (iPS) cells to an effective amount of at least one compound described herein to differentiate the stem cells into the endoderm cells such as definitive endoderm cells. Differentiated endoderm cells produced by the methods disclosed herein can be differentiated into pancreatic epithelium, and other endoderm derivatives such as thymus, liver, stomach, intestine and lung. Another aspect of the present invention relates to a method of producing pancreatic progenitor cells, such as Pdx1-positive pancreatic progenitor cells by exposing endoderm cells, such as definitive endoderm cells to an effective amount of at least one compound described herein to differentiate the definitive endoderm cells into Pdx1-positive pancreatic progenitor cells. Kits and compositions comprising Pdx1-positive pancreatic progenitor produced using the methods are also described.

Compositions and methods for promoting the generation of definitive endoderm

In recognition of the need to develop novel therapeutic agents and efficient methods for the synthesis thereof, the present invention provides novel bifunctional, trifunctional, or multifunctional compounds for inhibiting histone deacetylases, and pharmaceutically acceptable salts and derivatives thereof. The present invention further provides methods for treating disorders regulated by histone deacetylase activity (e.g., proliferative diseases, cancer, inflammatory diseases, protozoal infections, hair loss, etc.) comprising administering a therapeutically effective amount of an inventive compound to a subject in need thereof. The present invention also provides methods for preparing compounds of the invention.

Bifunctional histone deacetylase inhibitors

Certain embodiments disclosed herein are directed to a method of producing endoderm cells, such as definitive endoderm cells by exposing stem cells such as embryonic stem cells or induced pluripotent stem (iPS) cells to an effective amount of at least one compound described herein to differentiate the stem cells into the endoderm cells such as definitive endoderm cells. Differentated endoderm cells produced by the methods disclosed herein can be differentiated into pancreatic epithelium, and other endoderm derivatives such as thymus, liver, stomach, intestine and lung. Another aspect of the present invention relates to a method of producing pancreatic progenitor cells, such as Pdx1-positive pancreatic progenitor cells by exposing endoderm cells, such as definitive endoderm cells to an effective amount of at least one compound described herein to differentiate the definitive endoderm cells into Pdx1-positive pancreatic progenitor cells. Kits and compositions comprising Pdx1-positive pancreatic progenitor produced using the methods are also described.

The present invention provides novel compounds of formula (I) and pharmaceutical compositions thereof. The inventive compounds are useful as deacetylase inhibitors (e.g., histone deacetylase inhibitors) and may be useful in the treatment of proliferative diseases such as cancer. In particular, the inventive compounds are HDAC6 inhibitors. The invention also provide synthetic methods for preparing the inventive compounds.

The invention relates to methods and products for enhancing and improving recovery of lost memories. In particular the methods are accomplished through the increase of histone acetylation.

Growing community of inventors

Middleton, WI, United States of America

Weiping Tang