7-BENZYL-4-(2-METHYLBENZYL)-2,4,6,7,8,9-HEXAHYDROIMIDAZO [1,2-a]PYRIDO[3,4-e]PYRIMIDIN-5(1H)-ONE, ANALOGS THEREOF, AND SALTS THEREOF AND METHODS FOR THEIR USE IN THERAPY

A method of treating a condition in a subject, comprising:

• (i) over a first time interval, administering a plurality of doses of a therapeutic agent including compound (1):
• an analog thereof, or a pharmaceutically acceptable salt of compound (1) or an analog thereof, wherein the plurality of doses is administered over a second time interval within the first time interval;
• and
• (ii) repeating step (i) one or more additional times.

A method of treating a disease or condition in a human or animal subject in need of such treatment, the method comprising:

• (i) administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of compound (1):
• or a pharmaceutically acceptable salt thereof;
• and
• (ii) monitoring levels of compound (1), the pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of compound (1) or a pharmaceutically acceptable salt thereof is selected to maintain a concentration of compound (1), the pharmaceutically acceptable salt thereof, or the metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject is at least about 400 ng/mL for a therapeutic time period within 4 hours post-treatment.

A method of treating a disease or condition in a human or animal subject in need of such treatment, the method comprising:

• (i) administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of compound (1):
• or a pharmaceutically acceptable salt thereof;
• and
• (ii) monitoring levels of compound (1), the pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling, wherein dosing of compound (1) or a pharmaceutically acceptable salt thereof is selected to obtain an AUC of compound (1), the pharmaceutically acceptable salt thereof, or the metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject is at least about 3,500 hr-ng/mL with a time period of 24 or 48 hours post-treatment or extrapolated to infinity.

A method of treating a disease or condition in a human or animal subject in need of such treatment, the method comprising:

• (i) administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of compound (1):
• or a pharmaceutically acceptable salt thereof;
• and
• (ii) monitoring levels of compound (1), the pharmaceutically acceptable salt thereof, or a metabolite thereof in the subject using pharmacokinetic profiling,
• wherein dosing of compound (1) or a pharmaceutically acceptable salt thereof is selected to result in undetectable concentrations of compound (1), the pharmaceutically acceptable salt thereof, or the metabolite thereof in whole blood, plasma, serum, or cerebrospinal fluid of the subject at 3 days, 4 days, 5 days, 6 days, or 7 days post-treatment.

A method of identifying whether a subject having cancer is likely to be responsive to administration of compound (1), comprising:

• (i) obtaining a biological sample from the subject;
• (ii) measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, or DR5 in the sample;
• (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard;
• and
• (iv) determining whether the subject is likely to be responsive to administration of compound (1), based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.

A method of assessing the effectiveness of or monitoring a subject having cancer and undergoing administration of compound (1), comprising:

• (i) obtaining a biological sample from the subject;
• (ii) measuring expression, post-translational modifications, or activity levels of or mutations in eIF2-alpha, ATF4, CHOP, DR5, or cleaved or total cytokeratin 18 in the sample;
• (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard;
• and
• (iv) determining whether the subject is responsive to administration of compound (1), based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.

A method of identifying whether a subject having cancer is likely to be responsive to administration of compound (1), comprising:

• (i) obtaining a biological sample from the subject;
• (ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample;
• (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard;
• and
• (iv) determining whether the subject is likely to be responsive to administration of compound (1), based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.

A method of assessing the effectiveness of or monitoring a subject having cancer and undergoing administration of compound (1), comprising:

• (i) obtaining a biological sample from the subject;
• (ii) measuring expression, post-translational modifications, or activity levels of or mutations in at least one dopamine receptor in the sample;
• (iii) comparing the levels measured and/or the mutations found in the sample to those for a pre-determined standard;
• and
• (iv) determining whether the subject is responsive to administration of compound (1), based on the levels measured and/or mutations found in the sample to those for the pre-determined standard.

A method for screening a potential cancer therapeutic, comprising:

• (i) contacting at least one G protein-coupled receptor (GPCR) with a test compound suspected of being a cancer therapeutic;
• (ii) measuring the binding affinity, interaction or GPCR signalling of the test compound to the GPCR;
• and
• (iii) comparing the binding affinity or interaction of test compound to a pre determined threshold, wherein GPCR antagonism or GPCR signaling antagonism of the test compound comparable to or greater than the threshold is indicative of a cancer therapeutic.

A method for screening a potential cancer therapeutic, comprising:

• (i) contacting at least one dopamine receptor with a test compound suspected of being a cancer therapeutic;
• (ii) measuring the binding affinity or interaction of the test compound to the at least one dopamine receptor;
• and
• (iii) comparing the binding affinity or interaction of the test compound to a pre determined threshold, wherein inhibition of the at least one dopamine receptor by the test compound comparable to or greater than the threshold is indicative of a cancer therapeutic.

A method for screening a potential cancer therapeutic using a processor, comprising:

• (i) using a computational docking method to model binding or interaction, if any, of one or more 3-dimensional structures of a test molecule suspected of being a cancer therapeutic to a 3-dimensional structure or model of at least one dopamine receptor;
• (ii) using the computational method to estimate the binding affinity or interaction of the test molecule structure to the structure of the at least one dopamine receptor;
• and
• (iii) using the computational method to compare the binding affinity or interaction of the test molecule to a pre-determined threshold, wherein inhibition of the at least one dopamine receptor by the test compound comparable to or greater than the threshold is indicative of a cancer therapeutic.