Latest Small Molecule to Emerge from GPR65 Discovery Program Counteracts Immunosuppressive Polarization of Macrophages Triggered by an Acidic Tumor Microenvironment (TME)
Drives Infiltration of T Cells and NK Cells into TME Leading to Impressive Anti-Tumor Activity in Preclinical Cancer Models Following Oral Dosing
OXFORD, UK I April 17, 2023 I Pathios Therapeutics Limited (“Pathios”), a biotech company focused on the development of first-in-class therapies for cancer, today announced the presentation of the latest preclinical data from the company’s GPR65 discovery program at the American Association for Cancer Research (AACR) Annual Meeting 2023. The presentation included the public unveiling of PTT-4256, an internally discovered, oral, highly potent, and selective small molecule inhibitor of GPR65 that has demonstrated excellent drug-like properties and impressive monotherapy anti-tumor activity in preclinical models. The data were featured in a poster presentation at the AACR annual meeting, being held April 14-19, 2023, in Orlando, Florida.
Pathios is pursuing a novel immuno-oncology approach to the treatment of cancer focused on counteracting the immunosuppressive polarization of tumor associated macrophages (TAMs) that is triggered by a highly acidic tumor microenvironment (TME). It does so by targeting GPR65, an acid sensing G protein-coupled receptor that is exclusively expressed on immune cells and is associated with driving the immunosuppressive TAM phenotype that prevents immune-mediated killing of cancer cells. Pathios’ internal human genetic analysis demonstrates that reductions in GPR65 function are associated with significantly improved survival across a range of solid tumor types, positioning it as a unique immuno-oncology target for therapeutic intervention.
Data presented at AACR highlighted the company’s discovery and advancement of PTT-4256, which exhibits high potency for GPR65 (IC50 < 1 nM in human macrophages) and more than a 500-fold selectivity for GPR65 over related receptors. In preclinical experiments, PTT-4256 was shown to be highly effective in counteracting the effects of low pH (i.e. high acidity) that polarizes human and mouse macrophages toward an immunosuppressive state. This PTT-4256-induced relief of immune suppression was associated with dose-dependent increases in a range of pro-inflammatory genes that are consistent with an anti-tumor immune response, evidence of an infiltration of T cells and natural killer (NK) cells into the TME, and prevention of the activation of immunosuppressive cytokines. Together, this activity led to impressive monotherapy efficacy for PTT-4256 in syngeneic mouse cancer models following oral dosing.
“Pathios’ identification of PTT-4256 represents the culmination of several years of diligent and sophisticated drug discovery work by our team of scientists. These efforts have produced a highly optimised compound supported by an extensive dataset illustrating that the molecule possesses all target attributes for testing our GPR65 inhibitor hypothesis in humans,” said Stuart Hughes, Ph.D., chief executive officer of Pathios. “Based on these latest data, we are now focused on completing the toxicology program that will support initiation of clinical trials in 2024. As we look ahead to our entry into the clinic, we continue to be utterly compelled by the promise of this novel immuno-oncology target, in particular noting the human genetic validation which we believe sets GPR65 inhibition apart from other approaches in the field.”
About Acidity in the Tumor Microenvironment
The acidic tumor microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumor associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes.
About Pathios Therapeutics
Launched in 2017, Pathios is a drug discovery and development company focused on translating innovative science into new medicines. Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs, and clinicians. The company is focused on developing small-molecule inhibitors of the pH-sensing G protein-coupled receptor GPR65 to target immunosuppressive macrophages in advanced cancers. To date, Pathios has secured a total of US$33M in Series A funding from the leading venture capital firms, Canaan Partners and Brandon Capital. Pathios is headquartered at the Innovation Centre on Milton Park, a key science precinct south of Oxford, UK.
For more information, please visit www.pathios.com.
SOURCE: Pathios Therapeutics
Post Views: 30
Latest Small Molecule to Emerge from GPR65 Discovery Program Counteracts Immunosuppressive Polarization of Macrophages Triggered by an Acidic Tumor Microenvironment (TME)
Drives Infiltration of T Cells and NK Cells into TME Leading to Impressive Anti-Tumor Activity in Preclinical Cancer Models Following Oral Dosing
OXFORD, UK I April 17, 2023 I Pathios Therapeutics Limited (“Pathios”), a biotech company focused on the development of first-in-class therapies for cancer, today announced the presentation of the latest preclinical data from the company’s GPR65 discovery program at the American Association for Cancer Research (AACR) Annual Meeting 2023. The presentation included the public unveiling of PTT-4256, an internally discovered, oral, highly potent, and selective small molecule inhibitor of GPR65 that has demonstrated excellent drug-like properties and impressive monotherapy anti-tumor activity in preclinical models. The data were featured in a poster presentation at the AACR annual meeting, being held April 14-19, 2023, in Orlando, Florida.
Pathios is pursuing a novel immuno-oncology approach to the treatment of cancer focused on counteracting the immunosuppressive polarization of tumor associated macrophages (TAMs) that is triggered by a highly acidic tumor microenvironment (TME). It does so by targeting GPR65, an acid sensing G protein-coupled receptor that is exclusively expressed on immune cells and is associated with driving the immunosuppressive TAM phenotype that prevents immune-mediated killing of cancer cells. Pathios’ internal human genetic analysis demonstrates that reductions in GPR65 function are associated with significantly improved survival across a range of solid tumor types, positioning it as a unique immuno-oncology target for therapeutic intervention.
Data presented at AACR highlighted the company’s discovery and advancement of PTT-4256, which exhibits high potency for GPR65 (IC50 < 1 nM in human macrophages) and more than a 500-fold selectivity for GPR65 over related receptors. In preclinical experiments, PTT-4256 was shown to be highly effective in counteracting the effects of low pH (i.e. high acidity) that polarizes human and mouse macrophages toward an immunosuppressive state. This PTT-4256-induced relief of immune suppression was associated with dose-dependent increases in a range of pro-inflammatory genes that are consistent with an anti-tumor immune response, evidence of an infiltration of T cells and natural killer (NK) cells into the TME, and prevention of the activation of immunosuppressive cytokines. Together, this activity led to impressive monotherapy efficacy for PTT-4256 in syngeneic mouse cancer models following oral dosing.
“Pathios’ identification of PTT-4256 represents the culmination of several years of diligent and sophisticated drug discovery work by our team of scientists. These efforts have produced a highly optimised compound supported by an extensive dataset illustrating that the molecule possesses all target attributes for testing our GPR65 inhibitor hypothesis in humans,” said Stuart Hughes, Ph.D., chief executive officer of Pathios. “Based on these latest data, we are now focused on completing the toxicology program that will support initiation of clinical trials in 2024. As we look ahead to our entry into the clinic, we continue to be utterly compelled by the promise of this novel immuno-oncology target, in particular noting the human genetic validation which we believe sets GPR65 inhibition apart from other approaches in the field.”
About Acidity in the Tumor Microenvironment
The acidic tumor microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumor associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes.
About Pathios Therapeutics
Launched in 2017, Pathios is a drug discovery and development company focused on translating innovative science into new medicines. Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs, and clinicians. The company is focused on developing small-molecule inhibitors of the pH-sensing G protein-coupled receptor GPR65 to target immunosuppressive macrophages in advanced cancers. To date, Pathios has secured a total of US$33M in Series A funding from the leading venture capital firms, Canaan Partners and Brandon Capital. Pathios is headquartered at the Innovation Centre on Milton Park, a key science precinct south of Oxford, UK.
For more information, please visit www.pathios.com.
SOURCE: Pathios Therapeutics
Post Views: 30
