Dana-farber-cancer Institute Inc.

Harvard College

Massachusetts Institute of Technology

The United States of America, As Represented by the Secretary, Department of Health and Human Services

The University of Chicago

Gregory H Bird

Loren D Walensky

Steven P Gygi

Wilhelm Haas

Martin Helmut Wuhr

Brian K Erickson

Craig Braun

Ruben Carrasco

Rosalind Segal

Sarah Elizabeth Raissi

Maria F Murphy

Stanley J Korsmeyer

Stuart H Orkin

Rida Mourtada

Evripidis Gavathiotis

Amy E Keating

Nico Tjandra

Motoshi Suzuki

Lisa Vaughn Goodrich

Rachel Guerra

Edward Harvey

Ann Morgan Cathcart

Raheleh Rezaei-Araghi

Rachel Eclov

James LaBelle

Nika N Danial

Lisa V Goodrich

Woojin Kim

Compositions and methods are provided for the treatment or prevention of chemotherapy-induced peripheral neuropathy and hearing loss in a subject in need thereof. The methods involve administering to the subject a bclw protein, a BH4 domain-containing fragment thereof, or a bclw mimetic. Also provided are exemplary bclw mimetics.

BCL-W polypeptides and mimetics for treating or preventing chemotherapy-induced peripheral neuropathy and hearing loss

This disclosure features structurally-stabilized and/or warhead-bearing structurally stabilized peptide inhibitors for targeting ubiquitin activating enzymes (E1). Also disclosed are methods of using such structurally-stabilized and warhead-bearing structurally stabilized peptides in the treatment of E1-expressing or -dependent cancers or diseases. Also provided are combination therapies comprising such structurally-stabilized and/or warhead-bearing structurally stabilized peptide for the treatment of E1-expressing or -dependent diseases.

Selective targeting of ubiquitin- and ubiquitin-like E1-activating enzymes by structurally-stabilized peptides

Provided herein are peptide-based therapeutics that target FOXP3 and methods of use thereof to decrease the immuno-suppressive effects of Tregs and inhibit immune dysregulation, while sparring inhibition of activated cytotoxic T cells, for example, in the context of anti-tumor immune responses, autoimmunity, inflammatory conditions, etc.

Compositions and methods for inhibition of FOXP3

In some embodiments, a mass spectrometry tag may comprise a linker region, a mass balance region, and a reporter region. The mass spectrometry tag may be configured to fragment in a mass spectrometer via an energy dependent process to produce multiple reporter molecules. For example, the reporter region of the tag may be configured to produce at least two reporter molecules via fragmentation. In some embodiments, one or more regions of the tag may comprise at least one heavy isotope. In some such embodiments, the ability to fragment into multiple reporter molecules as well as the placement and/or number of heavy isotope(s) allows the mass spectrometry tag to be distinguished from other similar mass spectrometry tags. In some such embodiments, the ability to distinguish between tags having the same or substantially similar total mass to charge ratio and reporter region mass may allow the system to have a greater multiplexing capacity than conventional systems.

Reagents for quantitative mass spectrometry

This disclosure features structurally-stabilized and/or cysteine-reactive peptide inhibitors for selective targeting of BFL-1, or dual targeting of BFL-1 and MCL-1. Also disclosed are methods of using such structurally-stabilized and cysteine-reactive peptides in the treatment of BFL-1- and/or MCL-1-expressing or -dependent cancers or diseases of cellular excess (e.g., autoimmune or inflammatory conditions). Also provided are combination therapies comprising such structurally-stabilized and/or cysteine-reactive peptides and inhibitors of the DNA damage response pathway, such as an ATM kinase inhibitor, ATR kinase inhibitor, CHK1/2 inhibitor, or PARP inhibitor; or an inhibitor of MCL-1, or a selective inhibitor of BCL-2, or an inhibitor of BCL-2/BCL-XL, for the treatment of BFL-1-expressing or -dependent cancers (e.g., AML), BFL-1 and MCL-1-expressing or -dependent cancers, or diseases of cellular excess (e.g., autoimmune or inflammatory conditions).

Selective targeting of apoptosis proteins by structurally-stabilized and/or cysteine-reactive NOXA peptides

Bcl-w polypeptides and mimetics for treating or preventing chemotherapy-induced peripheral neuropathy and hearing loss

The invention provides structurally-constrained peptides by hydrocarbon stapling of a BCL9 HD2 helix for use as a therapeutic agent. The invention further provides methods and kits for use of the structurally-constrained peptide of the instant invention. The invention is based, at least in part, on the results provided herein demonstrating that hydrocarbon stapled helical peptides display excellent proteolytic, acid, and thermal stability, restore the native helical structure of the peptide, possess superior pharmacokinetic properties compared to the corresponding unmodified peptides, and are highly effective in binding to &#x3b2;-catenin in vitro, in cellulo, and in vivo, disrupting the BCL9/&#x3b2;-catenin interaction, and thereby interfering with deregulated Wnt/&#x3b2;-catenin signaling for therapeutic benefit in a variety of human diseases including human cancer.

Targeting deregulated Wnt signaling in cancer using stabilized alpha-helices of BCL-9

Provided herein are stabilized peptides that bind Mcl-1. Also provided are compositions containing these polypeptides and methods of using such peptides in the treatment of cancer that include administering to a subject one of the polypeptides.

Selective Mcl-1 binding peptides

This disclosure features stapled peptide inhibitors (e.g., cysteine-reactive stapled peptides) of the anti-apoptotic protein, BFL-1, and methods of using same in the treatment of BFL-1 expressing cancers.

Peptides binding to Bfl-1

The invention provides composition and therapeutic, methods for modulating homeostatic pathways that are useful in treatment, and prevention of diabetes, diabetes associated disorders, metabolic disorders and cancer.

Methods of modulating cellular homeostatic pathways and cellular survival

The invention provides structurally-constrained peptides by hydrocarbon stapling of a BCL9 HD2 helix for use as a therapeutic agent. The invention further provides methods and kits for use of the structurally-constrained peptide of the instant invention. The invention is based, at least in part, on the results provided herein demonstrating that hydrocarbon stapled helical peptides display excellent proteolytic, acid, and thermal stability, restore the native helical structure of the peptide, possess superior pharmacokinetic properties compared to the corresponding unmodified peptides, and are highly effective in binding to &#x3b2;-catenin in vitro, in cellulo, and in vivo, disrupting the BCL-9/&#x3b2;-catenin interaction, and thereby interfering with deregulated Wnt/&#x3b2;-catenin signaling for therapeutic benefit in a variety of human diseases including human cancer.

The present invention provides stably crosslinked insulinotropic polypeptides having superior and unexpected benefits in the treatment of conditions involving abnormal glucose homeostasis, e.g., type 2 diabetes and conditions relating to type 2 diabetes. Such benefits include, but are not limited to, extended polypeptide half-life, enhanced alpha-helicity, improved thermal stability and protease resistance, increased functional activity and pharmacologic properties, improved bioavailability when administered by any route, and improved bioavailability and gastrointestinal absorption when delivered orally, as compared to the corresponding unmodified polypeptides. The invention also provides compositions for administering the polypeptides of the invention, as well as methods for preparing and evaluating the polypeptides of the invention.

Stabilized insulinotropic peptides and methods of use

Growing community of inventors

Pelham, NH, United States of America

Gregory H Bird