The present application is directed to a method of inhibiting proliferation of chromosome instable cancer cells. This method involves administering, to a population of cancer cells comprising chromosome instable cancer cells, an inhibitor of Kinesin Family Member 18A (KIF18A) at a dosage effective to inhibit proliferation of said chromosome instable cancer cells. The inhibitors of KIF18A may also be used in a method treating cancer in a subject. This method involves selecting a subject having cancer, where the cancer is characterized by chromosomal instability, and administering to the subject an inhibitor of KIF18A at a dosage effective to treat the cancer in the subject. Also disclosed is a combination therapeutic including an inhibitor of Kinesin Family Member 18A (KIF18A) and agent that promotes microtubule turnover or a cyclin-dependent kinase (CDK) inhibitor.

The present application is directed to a method of inhibiting proliferation of chromosome instable cancer cells. This method involves administering, to a population of cancer cells comprising chromosome instable cancer cells, an inhibitor of Kinesin Family Member 18A (KIF18A) at a dosage effective to inhibit proliferation of said chromosome instable cancer cells. The inhibitors of KIF18A may also be used in a method treating cancer in a subject. This method involves selecting a subject having cancer, where the cancer is characterized by chromosomal instability, and administering to the subject an inhibitor of KIF18A at a dosage effective to treat the cancer in the subject. Also disclosed is a combination therapeutic including an inhibitor of Kinesin Family Member 18A (KIF18A) and agent that promotes microtubule turnover or a cyclin-dependent kinase (CDK) inhibitor.

The present invention relates to the technical field of medicines. Specifically disclosed is a compound as represented by formula I′, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, symbols therein being as defined in the claims. The compound of the present invention may be used as a drug for regulating RET kinase activity or treating RET-related diseases, and has good pharmacokinetic properties.

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The present disclosure reports that pharmacological or genetic inhibition of Moloney murine leukemia virus insertion site 1 (BMI1) not only helped to eliminate BMI1+ cancer stem cells (CSCs), but can also augment PD1 blockade by strongly induced tumor cell-intrinsic immune responses by recruiting and activating CD8+ T cells. Taken together, the results indicate that in addition to purging CSCs, targeting BMI1 would enable immune checkpoint blockade to inhibit metastatic tumor growth and prevent tumor relapse by activating cell-intrinsic immunity.

The present disclosure reports that pharmacological or genetic inhibition of Moloney murine leukemia virus insertion site 1 (BMI1) not only helped to eliminate BMI1+ cancer stem cells (CSCs), but can also augment PD1 blockade by strongly induced tumor cell-intrinsic immune responses by recruiting and activating CD8+ T cells. Taken together, the results indicate that in addition to purging CSCs, targeting BMI1 would enable immune checkpoint blockade to inhibit metastatic tumor growth and prevent tumor relapse by activating cell-intrinsic immunity.

Provided herein are methods of treating cartilage disorders in a subject using a dual CLK/DYRK inhibitor, or a pharmaceutically acceptable salt of solvate thereof, or a combination of a CLK inhibitor, or a pharmaceutically acceptable salt of solvate thereof, and DYRK inhibitor or, pharmaceutically acceptable salt or solvate thereof.

Provided herein are methods of treating cartilage disorders in a subject using a dual CLK/DYRK inhibitor, or a pharmaceutically acceptable salt of solvate thereof, or a combination of a CLK inhibitor, or a pharmaceutically acceptable salt of solvate thereof, and DYRK inhibitor or, pharmaceutically acceptable salt or solvate thereof.

The present disclosure generally relates to a method of improving cognition and/or treating cognitive decline in a cognitively healthy subject comprising administering to the cognitively healthy subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as described herein.

The present disclosure generally relates to a method of improving cognition and/or treating cognitive decline in a cognitively healthy subject comprising administering to the cognitively healthy subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as described herein.

A novel prophylactic agent or therapeutic agent for functional gastrointestinal disorders or xerostomia is provided. The present invention is a therapeutic agent or prophylactic agent for functional gastrointestinal disorders, containing an azabenzimidazole compound represented by the following formula [1] (each symbol in the formula is as described in the specification), or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient.

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