Small molecule inhibitors of GPCR GPR68 and related receptors for treating cancer, glioblastoma, and other indications
Inventors
Hong, Charles C. • Williams, Charles H. • SINGH, Latur Ravithej
Assignees
University of Maryland Baltimore
Publication Number
US-12194027-B2
Publication Date
2025-01-14
Expiration Date
2040-04-17
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Abstract
The invention relates to a class of small molecule inhibitors of GPR68/OGR1, a proton-sensing/stretch-sensing/sheer-stress-sending G-protein coupled receptor, and related receptors GPR4 and GPR65. These inhibitors are useful as a therapeutic for glioblastoma and other neoplasms, as a monotherapy or adjuvant, and also can be used as a treatment for other conditions, such as osteoporosis, inflammatory bowel disease, autoimmune and chronic inflammatory diseases such as multiple sclerosis and inflammatory pain syndromes, GERD, aspiration pneumonitis, bacterial and viral pneumonia, COPD, acute respiratory distress syndrome (ARDS), and COVID-19.
Core Innovation
The invention relates to a novel class of small molecule inhibitors targeting GPR68/OGR1, a proton-sensing, stretch-sensing, and sheer-stress-sensing G-protein coupled receptor, along with related receptors GPR4 and GPR65. These inhibitors utilize a 1,2-dihydro-3′H-spiro[indole-3,2′-(1,3,4}thiadiazole]-2-one scaffold, with specific variable substitutions, to modulate the activity of these receptors. The compounds are suitable for formulation as pharmaceutical compositions and can be used alone or in combination with other therapeutic agents.
The invention addresses the problem stemming from the pathological effects of tissue acidification in cancer and inflammatory diseases. In cancer, particularly malignant and metastatic types, an acidotic extracellular environment results from increased glycolytic metabolism, creating conditions that promote tumor progression. Current therapies do not adequately target the cell signaling mechanisms driven by acidification, such as those mediated by GPR68 and related receptors.
By inhibiting GPR68/OGR1 and related receptors, the invention provides a therapeutic strategy for conditions characterized by high extracellular proton concentrations, including glioblastoma, other neoplasms, osteoporosis, inflammatory bowel disease, autoimmune diseases (such as multiple sclerosis), inflammatory pain syndromes, asthma, COPD, aspiration pneumonia, viral and bacterial pneumonias, ARDS, and COVID-19. The inhibitors may be used in monotherapy or as an adjunct to established treatments, such as anticancer agents like Temozolomide, to enhance efficacy or address unmet clinical needs associated with the pathophysiological roles of GPR68 signaling.
Claims Coverage
The patent contains one independent claim which outlines the main inventive features regarding methods for treating or preventing malignancy in mammals through administration of specific GPR68 inhibitors.
Method of treating or preventing malignancy using GPR68 inhibitors
A method involving the administration of a 1,2-dihydro-3′H-spiro[indole-3,2′-(1,3,4}thiadiazole]-2-one agent, or a salt thereof, to a mammalian subject in need, for treating or preventing malignancy. - The compounds have specific substitutions as defined in the patent (R1 is optionally substituted from —H, —CH3, —CH2CH3, —OCH3, —Br, —F, —CF3; R2 is —H or —CH3; R3 and R4 independently are —H, —CH3, —CH2CH3, —OCH3, —CN, —F, —COOCH3, —COOH, —SO2NH2). - Applicable to malignancies inclusive of glioblastoma, medulloblastoma, neuroendocrine prostate cancer, melanoma, skin cancer, breast cancer, ovarian cancer, kidney cancer, and lung cancer. - May optionally include co-administration with at least one additional therapeutic agent, e.g., anticancer agents such as Temozolomide.
The inventive features define a method of treating or preventing various malignancies in mammals using specifically substituted 1,2-dihydro-3′H-spiro[indole-3,2′-(1,3,4}thiadiazole]-2-one agents targeting GPR68, with possible combination therapy with other anticancer agents.
Stated Advantages
The inhibitors provide a logical and attractive therapeutic strategy by disrupting the pathologic loop involving acidification-induced GPR68 activation that contributes to disease progression in cancer and inflammatory conditions.
Unlike standard of care medications, GPR68 inhibitors are capable of targeting all three cardinal pathogenic processes in asthma: mucous hyperproduction, bronchoconstriction, and inflammation.
The compounds are effective in conditions for which the underlying mechanisms are not addressed by existing treatments, offering a new approach for disease modification in cancer, glioblastoma, chronic inflammatory, and autoimmune diseases.
The invention enables use both as monotherapy and as an adjuvant to enhance or synergize with existing therapeutic agents, such as Temozolomide and radiation therapy.
Documented Applications
Treatment and/or prevention of malignancies including glioblastoma, medulloblastoma, neuroendocrine prostate cancer, melanoma, skin cancer, breast cancer, ovarian cancer, kidney cancer, and lung cancer.
Therapy for osteoporosis.
Treatment and/or prevention of inflammatory bowel disease.
Treatment and/or prevention of autoimmune and chronic inflammatory diseases, such as multiple sclerosis and inflammatory pain syndromes.
Treatment of asthma, including poorly controlled asthma and acute exacerbations, alone or in combination with standard of care treatments.
Treatment and/or prevention of chronic obstructive pulmonary disease (COPD), chronic bronchitis, and reduction of airway mucous secretions.
Treatment and/or prevention of aspiration pneumonia, viral pneumonia, and coronavirus pneumonia (including COVID-19).
Prevention or treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), as well as reducing long-term sequelae such as lung fibrosis.
Potential co-administration with anticancer agents, such as Temozolomide, and with other therapies such as radiation.
Therapy for diabetes type 1, atherosclerosis, cardiovascular disease, and related inflammatory cardiovascular conditions.
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