GPR65 Modulating Compounds for Cancer and Autoimmune Therapy
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Solution Overview
Problem
Current therapies lack effective modulators for GPR65, a receptor involved in both tumour evasion and autoimmune diseases, which are associated with acidic microenvironments and inflammatory phenotypes.
Innovation Solution
Development of specific compounds that modulate GPR65 activity, including those of formula (I), (Ii), and (Ih), which are capable of altering the receptor's signaling pathways to treat proliferative disorders, immune disorders, asthma, and chronic obstructive pulmonary disease (COPD).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If GPR65 is activated by acidic microenvironment in tumour-associated macrophages, then cytoplasmic cAMP increases leading to ICER transcription, but this suppresses TNFα secretion and promotes tumour-permissive phenotype
Solution Approach 1:
The patent applies preliminary anti-action by developing GPR65 modulators that preemptively block the receptor's activation by acidic microenvironment. These compounds prevent the downstream signaling cascade (cAMP increase, ICER transcription) before it can promote tumour-permissive phenotype, thereby counteracting the harmful effect of GPR65 activation in cancer
Solution Approach 2:
The patent inverts the normal GPR65 signaling pathway by using modulators that activate GPR65 in a controlled manner to produce opposite effects in different contexts. In tumour-associated macrophages, activation is blocked; in autoimmune disease contexts, controlled activation may promote protective immune responses, effectively using the same receptor pathway for opposite therapeutic goals
2Object-affected harmful factors
If GPR65 acts through ICER in CD4+ T cells, then IL-2 secretion is suppressed biasing cells toward inflammatory Th17 phenotype, but this increases pathogenicity in autoimmune disease
Solution Approach 1:
The patent applies preliminary anti-action by using GPR65 modulators to prevent the receptor-mediated suppression of IL-2 and Th17 differentiation in CD4+ T cells. By blocking GPR65 activation before it can suppress IL-2, the compounds prevent the development of pathogenic Th17 cells that drive autoimmune disease
Solution Approach 2:
The patent uses GPR65 modulators as intermediary molecules that selectively interfere with the GPR65-ICER-IL-2 signaling axis in autoimmune contexts. These compounds act as mediators that can distinguish between pathological and protective immune responses, blocking harmful Th17 differentiation while preserving other immune functions
3Reliability
If no effective GPR65 modulators are available, then therapeutic intervention for cancer and autoimmune diseases is limited, but developing new compounds requires significant research investment
Solution Approach 1:
The patent applies segmentation by dividing the complex task of GPR65 modulation into manageable structural components. The disclosed compound series use a core pharmacophore structure with variable substituents that can be systematically optimized, allowing researchers to develop multiple analogs with different properties from a modular framework
Solution Approach 2:
The patent demonstrates universality by creating GPR65 modulators with broad therapeutic applicability across multiple disease indications. The same compound series can potentially treat both cancer (by blocking tumour-permissive macrophage polarization) and autoimmune diseases (by preventing pathogenic Th17 differentiation), maximizing the therapeutic value of the development investment
Data Source
AI summary
One aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, (I) ring A is an is optionally substituted 5 or 6 membered aromatic or heteroaromatic ring; Y is selected from CH2, C═N—OH, and CR10R10′; Ra and Rb are each independently selected from H and alkyl; Z is selected from O, S, NR17 and CR18; X is selected from O and NH; p is 0, 1 or 2; q is 0 or 1; and r is 0 or 1; wherein at least one of p, q and r is other than zero, and with the proviso that: (i) when r is 0, p is 1 and q is 1, when X is NH, Z is other than O; (ii) when r and q are both 0, and p is 1, Z is not O; R1, R4, and R5 are each independently selected from H, alkyl, alkoxy, OH, F, Cl, Br, and I; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, haloalkyl, haloalkoxy and CO2-alkyl; R10 and R10′ are each independently selected from H, F, alkyl, and haloalkyl; R15 and R16 are each independently selected from H, alkoxy, alkyl and OH; R17 is selected from H, CN, OH, alkoxy and alkyl; R18 is NO2 or CN; and wherein the compound is other than: (6S,9R)-10-benzyl-4-chloro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]-pyrimidine; (6S,9R)-10-benzyl-1,5,6,7,8,9-hexahydro-4H-6,9-epiminocyclohepta[d]pyrimidin-4-one; (6R,9S)-10-benzyl-1,5,6,7,8,9-hexahydro-4H-6,9-epiminocyclohepta[d]pyrimidin-4-one; 10-benzyl-1,5,6,7,8,9-hexahydro-4H-6,9-epiminocyclohepta[d]pyrimidin-4-one; 10-(2,4,6-trimethoxybenzyl)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]-pyrimidine; and 2-methoxy-5-((6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidin-10-yl)methyl)-benzonitrile. Further aspects of the invention relate to compounds of formula (I) for use in the field of immuno-oncology, immunology, and related applications.