The University of Texas System

Dana-farber-cancer Institute Inc.

Timothy P Heffernan

Philip Jones

Matthew Michael Hamilton

Michael J Soth

Jason P Burke

Maria Emilia Di Francesco

Kang Le

Christopher Lawrence Carroll

Barbara Czako

Timothy Joseph McAfoos

Gang Liu

Richard T Lewis

Jay Theroff

Zhijun Kang

Anne Yau

Zachary Herrera

Wylie S Palmer

Andrew John Phillips

Dennis Buckley

Georg Winter

Behnam Nabet

Justin Roberts

Jeffrey Kovacs

Christopher Bristow

Nakia Spencer

James Elliott Bradner

Richard Thomas Lewis

Alessia Petrocchi

Naphtali Reyna

Michelle Han

James Bradner

Carlo Toniatti

Timothy Mcafoos

Christopher A Bristow

Michael P Soth

Andrew J Phillips

Virginia Giuliani

Disclosed herein are methods of treating a tumor or cancer in a subject whose tumor or cancer cells express low levels of asparagine synthetase (ASNS), and compounds and compositions useful in such treatment. Also disclosed herein are methods of evaluating whether to administer a compound that inhibits glutathione production or a glutaminase inhibitor to a subject with a tumor or cancer.

Glutaminase inhibitor therapy

The present invention provides a means to modulate gene expression in vivo in a manner that avoids problems associated with CRISPR endogenous protein knock-out or knock-in strategies and strategies that provide for correction, or alteration, of single nucleotides. The invention includes inserting into the genome a nucleotide encoding a heterobifunctional compound targeting protein (dTAG) in-frame with the nucleotide sequence of a gene encoding an endogenously expressed protein of interest which, upon expression, produces an endogenous protein-dTAG hybrid protein. This allows for targeted protein degradation of the dTAG and the fused endogenous protein using a heterobifunctional compound.

Tunable endogenous protein degradation with heterobifunctional compounds

Disclosed herein are compounds and compositions useful in the treatment of GLS1 mediated diseases, such as cancer, having the structure of Formula I: Methods of inhibition GLS1 activity in a human or animal subject are also provided.

GLS1 inhibitors for treating disease

Disclosed herein are compounds of structural Formula VIIa or VIIb: or a pharmaceutically acceptable salt thereof, and compositions thereof useful in the treatment of GLS1 mediated diseases, such as cancer. Methods of inhibition GLS1 activity in a human or animal subject are also provided.

This invention is in the area of compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.

Regulating chimeric antigen receptors

Tunable endogenous protein degradation

Targeted protein degradation to attenuate adoptive T-cell therapy associated adverse inflammatory responses

Disclosed herein are compounds and compositions useful in the treatment of GLS1 mediated diseases, such as cancer, having the structure of Formula I:  Methods of inhibition GLS1 activity in a human or animal subject are also provided.

Growing community of inventors

Cambridge, MA, United States of America

Timothy P Heffernan