The General Hospital Corporation

Dana-farber-cancer Institute Inc.

The Broad Institute, Inc.

The Brigham and Women's Hospital, Inc.

University of Kansas

David E Fisher

Yanke Liang

Nisma Mujahid

Nathanael Schiander Gray

Hwan Geun Choi

Ramnik Xavier

Alykhan Shamji

Thomas Sundberg

Ryo Murakami

Rizwan Haq

Frank John Schoenen

Conor L Evans

Nathanael S Gray

Warren S Weiner

Patrick Faloon

Robert Smith

Hans Ragnar Widlund

Elisabeth Maria Roider

Sam Osseiran

Qing Yu Weng

Shinichiro Kato

Hequn Wang

Chong-Hyun Won

Eric Boyer

Thanh-Nga Tran

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

The present disclosure provides methods of increasing skin pigmentation in a subject in need thereof using salt-inducible kinase (SIK) inhibitors, such as macrocyclic compounds of Formula (I), bicyclic urea compounds of Formula (II), (III), and (IV), and compounds of Formula (V), (VI), (VI-A), or (VII). Also provided are pharmaceutical compositions, methods, and uses that include or involve a compound described herein.

Uses of pyrimidopyrimidinones as SIK inhibitors

This disclosure provides compositions and methods of treating cancer by inhibiting histone methyltransferases alone or in combination by synergistically inhibiting a histone demethylase, or a histone deacetylase (HDAC), or a bromodomain (BRD)-containing protein, or a B-Raf kinase. In particular, the cancers have deficient of SWI/SNF chromatin remodeling complexes because of mutations in one or more of the complex's subunit members.

Treatment of cancers having alterations within the SWI/SNF chromatin remodeling complex

The present disclosure provides methods of increasing skin pigmentation in a subject in need thereof using salt-inducible kinase (SIK) inhibitors, such as macrocyclic compounds of Formula (I), bicyclic urea compounds of Formula (II), (III), and (IV), and compounds of Formula (V), (VI), (VI-A), or (VII). Also provided are pharmaceutical compositions, methods, and uses that include or involve a compound described herein. 

Described herein are compositions comprising, and methods for using a composition comprising, Staphylococcal Exfoliative Toxin A (ETA) in an amount and duration sufficient to decrease the Stratum Corneum in a region of a subjects skin.

Compositions and methods for topical delivery of pharmaceutical agents

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. 

A system for visualizing melanin present in tissue can include an imaging system to record a signal based on a presence of melanin in tissue and a display device to display an image based on the signal. A first laser source can emit a Stokes pulse train and a second laser source can emit a pump pulse train. Both the first laser source and the second laser source comprise a tunable center wavelength or frequency. An energy difference between a frequency of the Stokes pulse train and a frequency of the pump pulse train is from 1750 cmto 2250 cm. The Stokes and the pump pulse train overlap in space and time. A scanning mechanism focuses the combined Stokes pulse train and pump pulse train within the tissue and scans across the tissue. A detector detects the signal based on a presence of melanin within the tissue.

Non-invasive visualization and quantification of natural pigments

Embodiments described here are combinatorial compositions and methods using these compositions for treating melanomas having activated mutations. The compositions comprises combinations of inhibitors of a MAPK pathway, ERK inhibitors, EGFR inhibitors, oxidative phosphorylation (OXPHOS) inhibitors, inhibitors of B-Raf, mitochondrial inhibitors, c-KIT inhibitors, MEK inhibitors and tigecycline or a derivative thereof.

Combinatorial compositions and methods for treatment of melanoma

Described herein are methods and compositions useful for enhancing pigmentation, such as skin, eye and/or hair pigmentation comprising administering e.g., an NNT inhibitor or an agent that modifies redox status in a melanocyte.

Methods and compositions for enhancing skin pigmentation

Provided herein are compounds of the formula (IV) as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful as MITF inhibitors, MITF pathway inhibitors and for the treatment of cancer. 

Inhibitors of the MITF molecular pathway

Microphthalmia (Mi) while present in melanocytes, a cells and osteoclast, is not normally present in other cells. We have found that Mi is present in the nucleus of melanoma cells. Melanoma can be diagnosed by contacting a malignant cell with a probe for Mi. If the probe identifies Mi in the nucleus of the cell, the cell is a melanoma.

Use of microphthalmia for diagnosis, prognosis and/or treatment of melanoma

Microphthalmia (Mi) while present in melanocytes, a cells and osteoclast, is not normally present in other cells. We have found that Mi is present in the nucleus of melanoma cells. Melanoma can be diagnosed by contacting a malignant cell with a probe for Mi. If the probe identities Mi in the nucleus of the cell, the cell is a melanoma.

Growing community of inventors

Newton, MA, United States of America

David E Fisher