Customer Background<\/h2>\n\n\n\n\n\nCorcept Therapeutics, located in Menlo Park, CA, is a leader in the discovery and development of drugs that regulate the effects of cortisol. Corcept\u2019s scientific expertise surrounding the regulation of cortisol has led to the discovery of an extensive library of novel compounds that may ultimately address life-threatening diseases such as Cushing\u2019s syndrome, caused by excessive activity of cortisol, and cancer, including prostate and pancreatic cancers.<\/p>\n<\/div>\n\n\n\n
\n\t \n\t\n\t\t\t\t\t\t\n\t\t \t\t\n\t\t\t\t\t\t\t\n\t\t\t\n\n![\"\"](\"https:\/\/www.sygnaturediscovery.com\/wp-content\/uploads\/2018\/03\/corcept_logo.webp\")
<\/figure>\n\n<\/div>\n\t\t\n\t <\/section>\n<\/div>\n<\/div>\n\n\n\nThe Challenge<\/h2>\n\n\n\n
The client was looking to prepare novel, selective glucocorticoid receptor antagonists (GR antagonists) with the potential to treat CNS disorders, cancers and\/or metabolic diseases. Compounds needed to show selectivity for the glucocorticoid receptor versus other Nuclear Hormone receptors. The integrated project team was tasked with medicinal chemistry design and synthesis, including overcoming challenges related to hERG inhibition, PK and potency. The team were also required to establish a comprehensive, tailored screening cascade as well as looking at biomarker identification and validation.<\/p>\n\n\n\n
Why Sygnature Discovery?<\/h2>\n\n\n\n
Sygnature\u2019s strong track record and ability to provide an integrated medicinal chemistry, in vitro<\/em> biology and ex vivo<\/em> biomarker platform set the stage for a successful collaboration. Key factors included Sygnature\u2019s innovative scientists, able to design and deliver candidate molecules for clinical development while working effectively and efficiently with other external partners (e.g., in vivo<\/em> PK\/PD profiling).<\/p>\n\n\n\nSygnature\u2019s Approach and Solution<\/h2>\n\n\n\n
Our long-term integrated drug discovery collaboration with Corcept began at the lead optimisation phase. Our scientists delivered innovative medicinal chemistry alongside a comprehensive, diverse screening cascade of\u00a0in vitro<\/em>\u00a0assays, including potency, selectivity, mode-of-action and\u00a0ex vivo<\/em>\u00a0biomarker.<\/p>\n\n\n\nLead compounds were further profiled in collaboration with our expert alliance partners, Saretius and Renasci (now part of Sygnature Discovery), to obtain pivotal\u00a0in vivo<\/em>\u00a0PK and PD data prior to advancing drug candidates into man.<\/p>\n\n\n\n\u00a0<\/p>\n\n\n\n\t \n\t\n\t\t\t\t\t\t\n\t\t \t\t\n\t\t\t\t\t\t\t\n<\/div>\n\t\t\t\t\t\n\t\t\t\n\n![\"\"](\"https:\/\/www.sygnaturediscovery.com\/wp-content\/uploads\/2025\/11\/10.1.1-Corcept-image.png\")
<\/figure>\n\n<\/div>\n\t\t\n\t <\/section>\n\n\n\n<\/span><\/p>\n\n\n\n<\/p>\n\n\n\n
Key Results and Impact\u00a0<\/h2>\n\n\n\n
Sygnature has to date delivered two clinical development candidates to Corcept:<\/p>\n\n\n\n
\n- Relacorilant (Lifyorli\u2122<\/strong>, previously CORT125134)<\/strong> \u2013 an orally administered selective GR antagonist \u2013 successfully completed the pivotal Phase 3 ROSELLA trial in platinum-resistant ovarian cancer and reached major regulatory milestones. In March 2026, relacorilant received U.S FDA approval<\/strong>, in combination with nab-paciltaxel, marking the first approved selective glucocorticoid receptor antagonist in oncology. Regulatory submissions in other indications, including hypercortisolism, remain ongoing, and a MMA has been filed in Europe <\/strong>for ovarian cancer.<\/li>\n\n\n\n
- Exicorilant (previously CORT125281)<\/strong> \u2013 another oral, selective GR antagonist, has advanced into Phase I\/IIa clinical evaluation in metastatic castration-resistant prostate cancer following successful Phase I studies in healthy volunteers.<\/li>\n<\/ul>\n\n\n\n
In addition, Sygnature has also developed a novel patented biomarker assay of cortisol activation (WO 2016187347). This assay provided a method for assessing a clinical response to a glucocorticoid receptor antagonist (GRA) in a human subject and for diagnosing Cushing\u2019s syndrome.<\/p>\n\n\n\n
Sygnature\u2019s former Director of Chemistry, Dr Iain Walters, presented the discovery and first disclosure of CORT125134 at the prestigious 19th<\/sup>\u00a0Royal Society of Chemistry \/ Society of Chemical Industry Medicinal Chemistry Symposium (10th<\/sup>-13th<\/sup>\u00a0September 2017, Cambridge, UK)<\/p>\n\n\n\nWorking Relationship<\/h2>\n\n\n\n
Throughout the project, the Sygnature and Corcept teams worked in close partnership with each other and third-party contributors. Each team adapted quickly to emerging data through frequent project meetings. A shared alignment on goals, combined with Sygnature\u2019s integrated service model, allowed Corcept to maintain momentum and deliver in a timely manner.<\/p>\n\n\n\n
\n\n \n \n \n During a productive collaboration that has spanned several years, Sygnature Discovery has carried out first class medicinal and synthetic chemistry and\u00a0in vitro<\/em>\u00a0biology work. The commitment, flexibility and communication skills of the Sygnature scientists allowed us to quickly identify promising lead candidates, of which CORT125134 is the most advanced. We are looking forward to its further development<\/p>\n<\/div>\n <\/blockquote>\n \n \n \n \n Dr Hazel Hunt<\/h4>\n
VP, Research<\/p>\n <\/figcaption>\n<\/figure>\n\n <\/div>\n <\/div>\n \n <\/div>\n\n\n\n
<\/p>\n\n\n\n
Conclusions and Future Outlook <\/h2>\n\n\n\n
The collaboration between Sygnature Discovery and Corcept Therapeutics represents a compelling example of successful integrated drug discovery. With relacorilant having recieved U.S. FDA approval in ovarian cancer <\/strong>and additional regulatory submissions ongoing, and exicorilant progressing through early-stage oncology development<\/strong>, Corcept\u2019s programme continues to advance toward key clinical and regulatory milestones. These developments highlight the impact of the discovery effort and set the stage for the next phase of progression and both commercial and clinical success.<\/p>\n\n\n\n\u00a0<\/h2>\n\n\n\nPublications and Patents \u2013 Corcept and Sygnature<\/h2>\n\n\n\n
Hunt, Hazel J.; Belanoff, Joseph K.; Walters, Iain; Gourdet, Benoit; Thomas, Jennifer; Barton, Naomi; Unitt, John; Phillips, Timothy; Swift, Denise; Eaton, Emily.\u00a0The Identification of the Clinical Candidate (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-<\/a>pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1Hpyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134):\u2013 A Selective Glucocorticoid Receptor (GR) Antagonist.\u00a0Journal of Medicinal Chemistry (2017), 60(8), 3405-3421<\/span><\/p>\n\n\n\nBali, U., Phillips, T., Hunt, H., and Unitt,\u00a0J.\u00a0FKBP5 mRNA Expression Is a Biomarker for GR Antagonism<\/a>. Journal of Clinical Endocrinology & Metabolism (2016), 101(11), 4305-4312017), 60(8), 3405-3421.<\/span><\/p>\n\n\n\n
Corcept Therapeutics, located in Menlo Park, CA, is a leader in the discovery and development of drugs that regulate the effects of cortisol. Corcept\u2019s scientific expertise surrounding the regulation of cortisol has led to the discovery of an extensive library of novel compounds that may ultimately address life-threatening diseases such as Cushing\u2019s syndrome, caused by excessive activity of cortisol, and cancer, including prostate and pancreatic cancers.<\/p>\n<\/div>\n\n\n\n
<\/figure>\n\n<\/div>\n\t\t\n\t <\/section>\n<\/div>\n<\/div>\n\n\n\nThe Challenge<\/h2>\n\n\n\n
The client was looking to prepare novel, selective glucocorticoid receptor antagonists (GR antagonists) with the potential to treat CNS disorders, cancers and\/or metabolic diseases. Compounds needed to show selectivity for the glucocorticoid receptor versus other Nuclear Hormone receptors. The integrated project team was tasked with medicinal chemistry design and synthesis, including overcoming challenges related to hERG inhibition, PK and potency. The team were also required to establish a comprehensive, tailored screening cascade as well as looking at biomarker identification and validation.<\/p>\n\n\n\n
Why Sygnature Discovery?<\/h2>\n\n\n\n
Sygnature\u2019s strong track record and ability to provide an integrated medicinal chemistry, in vitro<\/em> biology and ex vivo<\/em> biomarker platform set the stage for a successful collaboration. Key factors included Sygnature\u2019s innovative scientists, able to design and deliver candidate molecules for clinical development while working effectively and efficiently with other external partners (e.g., in vivo<\/em> PK\/PD profiling).<\/p>\n\n\n\n Our long-term integrated drug discovery collaboration with Corcept began at the lead optimisation phase. Our scientists delivered innovative medicinal chemistry alongside a comprehensive, diverse screening cascade of\u00a0in vitro<\/em>\u00a0assays, including potency, selectivity, mode-of-action and\u00a0ex vivo<\/em>\u00a0biomarker.<\/p>\n\n\n\n Lead compounds were further profiled in collaboration with our expert alliance partners, Saretius and Renasci (now part of Sygnature Discovery), to obtain pivotal\u00a0in vivo<\/em>\u00a0PK and PD data prior to advancing drug candidates into man.<\/p>\n\n\n\n \u00a0<\/p>\n\n\n <\/span><\/p>\n\n\n\n <\/p>\n\n\n\n Sygnature has to date delivered two clinical development candidates to Corcept:<\/p>\n\n\n\n In addition, Sygnature has also developed a novel patented biomarker assay of cortisol activation (WO 2016187347). This assay provided a method for assessing a clinical response to a glucocorticoid receptor antagonist (GRA) in a human subject and for diagnosing Cushing\u2019s syndrome.<\/p>\n\n\n\n Sygnature\u2019s former Director of Chemistry, Dr Iain Walters, presented the discovery and first disclosure of CORT125134 at the prestigious 19th<\/sup>\u00a0Royal Society of Chemistry \/ Society of Chemical Industry Medicinal Chemistry Symposium (10th<\/sup>-13th<\/sup>\u00a0September 2017, Cambridge, UK)<\/p>\n\n\n\n Throughout the project, the Sygnature and Corcept teams worked in close partnership with each other and third-party contributors. Each team adapted quickly to emerging data through frequent project meetings. A shared alignment on goals, combined with Sygnature\u2019s integrated service model, allowed Corcept to maintain momentum and deliver in a timely manner.<\/p>\n\n\n\n During a productive collaboration that has spanned several years, Sygnature Discovery has carried out first class medicinal and synthetic chemistry and\u00a0in vitro<\/em>\u00a0biology work. The commitment, flexibility and communication skills of the Sygnature scientists allowed us to quickly identify promising lead candidates, of which CORT125134 is the most advanced. We are looking forward to its further development<\/p>\n<\/div>\n <\/blockquote>\n \n VP, Research<\/p>\n <\/figcaption>\n<\/figure>\n\n <\/div>\n <\/div>\n \n <\/div>\n\n\n\n <\/p>\n\n\n\n The collaboration between Sygnature Discovery and Corcept Therapeutics represents a compelling example of successful integrated drug discovery. With relacorilant having recieved U.S. FDA approval in ovarian cancer <\/strong>and additional regulatory submissions ongoing, and exicorilant progressing through early-stage oncology development<\/strong>, Corcept\u2019s programme continues to advance toward key clinical and regulatory milestones. These developments highlight the impact of the discovery effort and set the stage for the next phase of progression and both commercial and clinical success.<\/p>\n\n\n\n Hunt, Hazel J.; Belanoff, Joseph K.; Walters, Iain; Gourdet, Benoit; Thomas, Jennifer; Barton, Naomi; Unitt, John; Phillips, Timothy; Swift, Denise; Eaton, Emily.\u00a0The Identification of the Clinical Candidate (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-<\/a>pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1Hpyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134):\u2013 A Selective Glucocorticoid Receptor (GR) Antagonist.\u00a0Journal of Medicinal Chemistry (2017), 60(8), 3405-3421<\/span><\/p>\n\n\n\n Bali, U., Phillips, T., Hunt, H., and Unitt,\u00a0J.\u00a0FKBP5 mRNA Expression Is a Biomarker for GR Antagonism<\/a>. Journal of Clinical Endocrinology & Metabolism (2016), 101(11), 4305-4312017), 60(8), 3405-3421.<\/span><\/p>\n\n\n\nSygnature\u2019s Approach and Solution<\/h2>\n\n\n\n
<\/figure>\n\n<\/div>\n\t\t\n\t <\/section>\n\n\n\nKey Results and Impact\u00a0<\/h2>\n\n\n\n
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Working Relationship<\/h2>\n\n\n\n
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Dr Hazel Hunt<\/h4>\n
Conclusions and Future Outlook <\/h2>\n\n\n\n
\u00a0<\/h2>\n\n\n\n
Publications and Patents \u2013 Corcept and Sygnature<\/h2>\n\n\n\n