Abstract: The present invention provides compositions and methods for regulating pancreatic beta cell function through modulation of adipsin activity and/or expression. Also provided are methods for preventing, treating, diagnosing, and prognosing metabolic disorders, such as diabetes, in a subject through modulation or detection of adipsin activity and/or expression.

Abstract: The present invention provides novel compounds of Formula (I), (II), or (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g.

Abstract: Methods of generating and optimizing stabilized (e.g., stapled and/or stitched) anti-microbial peptides (StAMPs) for the prophylaxis and treatment of antibiotic-resistant (e.g., colistin-resistant, methicillin resistant, meropenem-resistant) bacterial infections (e.g., Gram-negative, Gram-positive), and methods for using such peptides for experimental investigation, livestock management, management of crops/trees/plants, and/or therapeutic benefit. Also featured are methods for reducing renal toxicity of a StAMP.

Abstract: 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.

Abstract: The present disclosure provides novel heteroaryl compounds of formula (VII). Such compounds are useful for the treatment of cancers.

Abstract: 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.

Abstract: The present disclosure relates to compositions and methods for the diagnosis and treatment or prevention of microsatellite unstable cancers. In particular, the instant disclosure provides for identification of a cancer as exhibiting microsatellite instability (MSI) and/or impaired mismatch repair (MMR), and selection and/or administration of an inhibitor of the WRN helicase as a therapeutic agent for such a cancer and/or subject having or at risk of developing such a cancer.

Abstract: The invention provides methods and devices for determining molecular signatures in a cancer that predict response to a MARPK pathway inhibitor and methods of use of such signatures.

Abstract: The present invention relates to methods of treating brain metastases using synergistic combinations of anti-PI3K and anti-mTOR therapies. It has also been determined that blocking PI3K and mTOR provides therapeutic benefit for treating brain metastases.

Abstract: The present disclosure provides compounds of Formula (I?) (e.g., compounds of Formula (I)), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase (e.g., Janus kinase (JAK), e.g., Janus kinase 2 (JAK2)) inhibitors. Also provided are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits (e.g., for treating a disease (e.g., proliferative disease) in a subject in need thereof).

Abstract: The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase (e.g., Janus kinase (JAK), e.g., Janus kinase 2 (JAK2)) inhibitors. Also provided are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits (e.g., for treating a disease (e.g., proliferative disease) in a subject in need thereof).

Abstract: 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.

Abstract: Provided herein are Toll-like receptor 2 (TLR2) agonists for use in enhancing human immune response and/or as adjuvants in vaccines. The TLR2 agonists include thiophenes, imidazoles, or phenyl-containing compounds, which may be compounds of Formulae (I), (II), (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. The compounds described herein are used as enhancers of an immune response (e.g., innate and/or adaptive immune response), and are useful in treating and/or preventing a disease, as adjuvants in a vaccine for the disease, (e.g., proliferative disease, inflammatory disease, autoimmune disease, infectious disease, or chronic disease). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein.

Abstract: The present invention provides bivalent inhibitors of BET bromodomains, such as compounds of Formulae (I), (II), (III), (IV), (V), and (VI). Some bromodomain-containing proteins (e.g., BRD4) have a tandem bromodomain primary structure comprising more than one bromodomain binding site (e.g., BRD4 comprises BD1 and BD2). Bivalent inhibitors of BET bromodomains provided herein can target bromodomains through advantageous multivalent interactions, and can therefore can be to treat diseases or conditions associated with bromodomain-containing proteins. The present also provides pharmaceutical compositions and kits comprising the inventive compounds, as well as methods of using the inventive compounds.

Abstract: The present invention provides compounds and pharmaceutically compositions thereof. The compounds and compositions are binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

Abstract: The present disclosure provides a self-contained system that contains a plurality of target cartridges, automatically inserts a selected target cartridge into position for irradiation, advances a foil to facilitate irradiation over the target chamber, replaces the foil for additional irradiation (if desired), serves as a dissolution cell for retrieval of the irradiated material, removes the used target cartridge and inserts a new cartridge for subsequent cycles of operation. Consequently, only the dissolved target material and dissolution medium are transferred between the target system and any post processing cells/labs. Accordingly, a system is disclosed for processing a target material without disturbance to irradiated material (thereby eliminating risk of impurities) and without requiring manual access/intervention (thereby eliminating risk of exposure).

Abstract: The present invention provides novel compounds of Formulae (I?) and (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g.

Abstract: Disclosed are macrocyclic compounds that possess inhibitory activity against DYRK, TRK, TLK, and/or RET. Also disclosed are pharmaceutical compositions containing the compounds, methods of making the compounds, and methods of using the compounds to treat diseases and disorders that are characterized or mediated by aberrant DYRK, TRK, TLK, and/or RET activity such as cancer, neurodegenerative disorders and genetic disorders.

Abstract: The present application provides bifunctional compounds of Formula (Ia) or (Ib): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 8 (CDK8). The present application also relates to methods for the targeted degradation of CDK8 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK8 which can be utilized in the treatment of disorders modulated by CDK8.

Abstract: The disclosure relates to pharmaceutical combinations comprising an HDAC6 selective inhibitor and a BET inhibitor for the treatment of cancer in a subject in need thereof. Also provided herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of an HDAC6 selective inhibitor and a BET inhibitor.