The disclosure relates generally to polyglutamated antifolates, formulations containing liposomes filled with the polyglutamated antifolates, methods of making the polyglutamated antifolates and liposome containing formulations, and methods of using the polyglutamated antifolates and liposome containing formulations to treat hyerproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., an autoimmune disease such as rheumatoid arthritis).

The compositions and methods of the invention provide compositions and methods for preferential targeting of tissues to delivery therapeutic or diagnostic agents. For example, such compounds are useful in the treatment of joint disorders those affecting articulating joints, e.g., injury-induced osteoarthritis as well as autoimmune diseases affecting joint tissue such as rheumatoid arthritis.

This invention provides heterocyclic compounds that bind to E3 Ubiquitin Ligase (typically through cereblon) (“Degrons”), which can be used as is or linked to a Targeting Ligand for a selected Target Protein for therapeutic purposes and methods of use and compositions thereof as well as methods for their preparation.

Described herein are protein-payload conjugates and compositions thereof that are useful, for example, for target-specific delivery of therapeutic and/or imaging agent moieties. In certain embodiments, provided are specific and efficient methods for producing protein-payload constructs (e.g., antibody-drug conjugates) utilizing a combination of transglutaminase and Diels-Alder techniques. Antibody-drug conjugates and compositions which comprise glutaminyl-modified antibodies, Diels-Alder adducts, and reactive payloads and are provided.

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a beta-ENaC (SCNN1B) gene. The beta-ENaC RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of a beta-ENaC gene. Pharmaceutical compositions that include one or more beta-ENaC RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described beta-ENaC RNAi agents to epithelial cells, such as pulmonary epithelial cells, in vivo, provides for inhibition of beta-ENaC gene expression and a reduction in ENaC activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including chronic obstructive pulmonary disease (COPD).

Drug conjugates having formula [D-(X).sub.b-(AA).sub.w-(T).sub.g-(L)-].sub.n-Ab wherein: D is a drug moiety having the following formula (I) or a pharmaceutically acceptable salt or ester thereof, wherein D is covalently attached via a hydroxy group at OR.sub.1, OR.sub.3 or ZH, or a thiol group at ZH to (X).sub.b if any, or (AA).sub.w if any, or to (T).sub.g if any, or (L); that are useful in the treatment of cancer.

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There are provided bivalent compounds and conjugates thereof, the conjugates comprising a bivalent compound, a targeting moiety, and a bioactive agent, as well as pharmaceutical compositions and methods of use of the conjugate for the treatment, inhibition, or prevention of diseases and disorders which are therapeutic targets of the bioactive agent.

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Compositions and methods for selective mTOR inhibition and/or increase of autophagy in a tissue of a subject have been developed for the treatment of cancer. Caged mTOR inhibitor prodrugs including photo-cleavable protecting groups are provided for selective chemotherapy through an optochemical treatment system. Pharmaceutical compositions of mTOR inhibitors that are deactivated (caged) with a photo-removable protecting group to controllably block the inhibitory activity of the inhibitor are provided. The photo-removable group is cleavable upon exposure to light irradiation, releasing the active inhibitor of mTOR signaling and autophagy at the site of irradiation. An exemplary caged mTOR inhibitor prodrug is a caged OSI-027 prodrug having a DEACM moiety bound thereto (cOSI-027). The cOSI-027 is activated in the region of a tumor by removal of the DEACM protecting group by exposure to light at 420 nm.

A compound of Formula I, ##STR00001##
and its analogs are provided. Compositions that include Formula I can be used to inhibit human equilibrative nucleoside transporter 1, increase adenosine signaling and produce effects that include increasing antiviral activity, increasing antiparasitic activity, increasing alcohol tolerance, decreasing pain protecting from ischemia as well as many other conditions.

The present disclosure provides compounds represented by Formula I: and the salts or solvates thereof, wherein R1, R3, L, Y, and B1 are as defined in the specification. Compounds having Formula I are SHP2 protein degraders useful for the treatment of cancer and other diseases.