Compounds of formulae (I) and (II), compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo.

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Compounds of formulae (I) and (II), compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo.

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A global effort is underway to identify compounds to treat emerging virus infections, such as COVID-19. Since de novo compound design is an extremely long, time-consuming, and expensive process, efforts are underway to discover existing compounds that can be repurposed for COVID-19 and new viral diseases. The present invention discloses a machine learning representation framework that uses deep learning-induced vector embeddings of compounds and viral proteins as features to predict compound-viral protein activity. The prediction model uses a consensus framework to rank approved compounds against viral proteins of interest.

A global effort is underway to identify compounds to treat emerging virus infections, such as COVID-19. Since de novo compound design is an extremely long, time-consuming, and expensive process, efforts are underway to discover existing compounds that can be repurposed for COVID-19 and new viral diseases. The present invention discloses a machine learning representation framework that uses deep learning-induced vector embeddings of compounds and viral proteins as features to predict compound-viral protein activity. The prediction model uses a consensus framework to rank approved compounds against viral proteins of interest.

An antitumor formulation comprising a biphenyl compound having LSD1 inhibitory activity or a salt thereof and one or more other antitumor agents that are administered in combination, the compound being represented by Formula (I): ##STR00001##
wherein ring A, ring B, R1 to R6, l, m, and n are as defined in the specification.

An antitumor formulation comprising a biphenyl compound having LSD1 inhibitory activity or a salt thereof and one or more other antitumor agents that are administered in combination, the compound being represented by Formula (I): ##STR00001##
wherein ring A, ring B, R1 to R6, l, m, and n are as defined in the specification.

Hippocampal lesions, including synaptic failure, are a defining pathology of Alzheimer's disease (AD). However, the molecular mechanisms that underlie hippocampal synaptic injury in this neurodegenerative disorder have yet not been fully elucidated. In Current therapeutic efforts for the treatment of AD are not effective in correcting hippocampal synaptic deficits. It is disclosed that the interaction with amyloid beta (Aβ) induces dysfunction of growth hormone secretagogue receptor 1a (GHSR1α; ghrelin receptor), leading to suppressed GHSR1α regulation of hippocampal dopamine receptor D1 (DRD1) in AD hippocampi. The modulation of DRD1 by GHSR1α impacts hippocampal synaptic plasticity. The simultaneous application of a selective GHSR1α agonist and a selective DRD1 agonist mitigates Aβ-induced hippocampal synaptic injury and improves spatial memory in AD mouse models. These data reveal a novel mechanism of hippocampal vulnerability in AD and that the combined activation of GHSR1α and DRD1 provides a new avenue for the pharmaceutical treatment of AD.

Hippocampal lesions, including synaptic failure, are a defining pathology of Alzheimer's disease (AD). However, the molecular mechanisms that underlie hippocampal synaptic injury in this neurodegenerative disorder have yet not been fully elucidated. In Current therapeutic efforts for the treatment of AD are not effective in correcting hippocampal synaptic deficits. It is disclosed that the interaction with amyloid beta (Aβ) induces dysfunction of growth hormone secretagogue receptor 1a (GHSR1α; ghrelin receptor), leading to suppressed GHSR1α regulation of hippocampal dopamine receptor D1 (DRD1) in AD hippocampi. The modulation of DRD1 by GHSR1α impacts hippocampal synaptic plasticity. The simultaneous application of a selective GHSR1α agonist and a selective DRD1 agonist mitigates Aβ-induced hippocampal synaptic injury and improves spatial memory in AD mouse models. These data reveal a novel mechanism of hippocampal vulnerability in AD and that the combined activation of GHSR1α and DRD1 provides a new avenue for the pharmaceutical treatment of AD.

A fixed-dose combination drug product formulated for oral delivery comprises a fixed 158.3 mg dose of clarithromycin, a fixed 13.3 mg dose of clofazimine and a fixed 40.0 mg dose of rifabutin. The fixed-dose combination drug product is sufficiently designed for use in treating pulmonary Mycobacterium avium Complex (MAC) disease in a subject in need thereof. A method for treating MAC disease in a human having MAC lung infection comprising orally administering, twice daily, about 475 mg of clarithromycin, about 40 mg of clofazimine and about 120 mg of rifabutin. A kit for treating pulmonary MAC disease in an individual having MAC lung infection comprises a supply of fixed-dose combination drug products, wherein each of the fixed-dose combination drug products comprise a fixed 158.3 mg dose of clarithromycin, a fixed 13.3 mg dose of clofazimine and a fixed 40.0 mg dose of rifabutin; and instructions for use.

A fixed-dose combination drug product formulated for oral delivery comprises a fixed 158.3 mg dose of clarithromycin, a fixed 13.3 mg dose of clofazimine and a fixed 40.0 mg dose of rifabutin. The fixed-dose combination drug product is sufficiently designed for use in treating pulmonary Mycobacterium avium Complex (MAC) disease in a subject in need thereof. A method for treating MAC disease in a human having MAC lung infection comprising orally administering, twice daily, about 475 mg of clarithromycin, about 40 mg of clofazimine and about 120 mg of rifabutin. A kit for treating pulmonary MAC disease in an individual having MAC lung infection comprises a supply of fixed-dose combination drug products, wherein each of the fixed-dose combination drug products comprise a fixed 158.3 mg dose of clarithromycin, a fixed 13.3 mg dose of clofazimine and a fixed 40.0 mg dose of rifabutin; and instructions for use.