The Broad Institute, Inc.

The General Hospital Corporation

Dana-farber-cancer Institute Inc.

Harvard College

Massachusetts Institute of Technology

The General Hosptial Corporation

Ramnik Xavier

Alykhan Shamji

Thomas Sundberg

Nathanael Schiander Gray

Yanke Liang

Hwan Geun Choi

David E Fisher

Nisma Mujahid

Stuart L Schreiber

Aviv Regev

Henry M Kronenberg

Alexander K Shalek

Jose Ordovas-Montanes

Moshe Biton

Hera Vlamakis

Rebecca H Herbst

Marc Wein

Christopher Smillie

Daniel B Graham

Nathanael S Gray

Orit Rozenblatt-Rosen

Jose R Perez

Emily Patricia Balskus

Karthik Shekhar

Douglas Kenny

Damian Plichta

Adam Haber

Curtis Huttenhower

Noga Rogel

Chengwei Luo

Elizaveta Leshchiner

Andrew Brantley Hall

Moran Yassour

Bernard Khor

Liv Johannessen

Michael Durney

Jason Rush

Zhifang Cao

The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

Bicyclic urea kinase inhibitors and uses thereof

A system and method for prediction of immunodominant epitopes is provided herein. MHCII peptidomics was used to discover complex bacterial epitopes and host antigen processing pathways. Novel insights into the features of antigenicity are leveraged to build an algorithm for prediction of immunodominant epitopes. Use of immunodominant epitopes is described.

Systems and methods for MHC class II epitope prediction

An atlas of intestinal epithelial cells, intestinal epithelial stem cells and intestinal immune cells identifies new cell populations, markers, networks, and responses to stimuli. Intestinal T cells drive intestinal epithelial cell differentiation and activity. Accordingly, disclosed are methods of modulating intestinal epithelial cell differentiation, maintenance and/or function, related methods for the treatment of disease, including IBD. Also disclosed are methods and kits for identifying cell types, their differentiation, homeostasis and activation.

Modulation of intestinal epithelial cell differentiation, maintenance and/or function through T cell action

The present disclosure provides methods of treating and/or preventing osteoporosis using salt-inducible kinase (SIK) inhibitors. Also provided are methods of using SIK inhibitors for increasing the function of osteocytes, increasing the number of osteoblasts, increasing the activity of osteoblasts, inhibiting the resorption of a bone, decreasing the number of osteoclasts, inhibiting the activity of osteoclasts, increasing the mass of a bone, down-regulating the expression of the gene SOST, and/or inhibiting the activity of sclerostin. The SIK inhibitors may be combined with Src inhibitors or CSF1R inhibitors. Exemplary SIK inhibitors include the compounds of the formula:

Uses of salt-inducible kinase (SIK) inhibitors for treating osteoporosis

The present invention provides for a human cell atlas of the colon from healthy and diseased subjects. The atlas was obtained by single sequencing of about 117,000 cells. The present invention discloses novel markers for cell types. Moreover, genes associated with disease are identified in the colon and colon specific cell types. The invention provides for diagnostic assays based on gene markers and cell composition, as well as target cell types that express genes associated with disease. Finally, disclosed are novel cell types and methods of quantitating, detecting and isolating the cell types.

Cell atlas of the healthy and ulcerative colitis human colon

This application provides for methods of treatment for IBD, especially in subjects who havespecies orgroup IBD strains as a component of their microbiome. The application also provides for methods of diagnosing IBD, as well as kits for use in the claimed methods.

Methods of treating and diagnosing IBD associated with r. gnavus and/or r. gnavus group IBD colonization

Microbes expressing cholesterol oxidoreductase (COR) proteins, methods of engineering the microbes expressing COR proteins, compositions and methods of using the microbes are provided.

Cholesterol reducing compositions and methods of use thereof

Disclosed herein are compounds for the treatment of inflammatory bowel disease. Additionally, provided herein are compositions and methods for using these compounds and compositions in the treatment of inflammatory bowel disease in a subject.

Compositions and methods for treating inflammatory bowel disease

A method for treating inflammation and/or autoimmune diseases comprises administering to a subject in need thereof, a composition comprising a CDK8 inhibitor. In another aspect, a method for increasing IL-10 production comprises administering to a subject in need thereof a CDK8 inhibitor. In another aspect, a method for enhancing Tcell differentiation, comprising administering a composition comprising a CDK8 inhibitor. In certain example embodiments, the subject suffers from an inflammatory bowel disease. In certain other example embodiments, the subject requires immunosuppression to prevent rejection following a transplantation procedure.

Use of CDK8 inhibitors to treat diseases of inflammation and autoimmunity

The present disclosure provides methods of treating and/or preventing osteoporosis using salt-inducible kinase (SIK) inhibitors. Also provided are methods of using SIK inhibitors for increasing the function of osteocytes, increasing the number of osteoblasts, increasing the activity of osteoblasts, inhibiting the resorption of a bone, decreasing the number of osteoclasts, inhibiting the activity of osteoclasts, increasing the mass of a bone, down-regulating the expression of the gene SOST, and/or inhibiting the activity of sclerostin. The SIK inhibitors may be combined with Src inhibitors or CSF I R inhibitors. Exemplary SIK inhibitors include the compounds of the formula: (I), (II), (III), (IV), (V) or (VI). 

The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein. 

The present disclosure provides methods of treating and/or preventing inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) using salt-inducible kinase (SIK) inhibitors, such as macrocyclic SIK inhibitors of Formula (I), imidazolyl SIK inhibitors of Formula (II), and urea and carbamate SIK inhibitors of Formula (III-A) (e.g., urea and carbamate SIK inhibitors of Formula (III)). 

Uses of salt-inducible kinase (SIK) inhibitors

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Brookline, MA, United States of America

Ramnik Xavier