PHD — IBD
Proline Hydroxylase (PHD) Inhibitors: Treatment of Inflammatory Bowel Disease (IBD) (IND-Enabling)
Assays Completed
Owned and Available for Licensing
In vivo efficacy studies
Combo study with Mesalamine, Anti-TNFα antibody and CsA
In vivo efficacy studies with single agent
In vivo PK studies
In vitro ADME studies
Developability/CMC
In vitro cell-based
Toxicology studies
Enzymatic
Target Rationale
Oxygen-sensitive Proline Hydroxylase (PHD) regulates Hypoxia-inducible factor (HIF-1α), which is known to be an important regulator of cellular oxygen homeostasis. Under hypoxic conditions, PHD is inhibited, leading to the accumulation of HIF-1α, translocation into the nucleus, and binding to HIF-1β to form a heterodimer that acts as a transcription factor thereby inducing mitophagy. HIF-1α was recognized as a protective regulator of Inflammatory Bowel Disease (IBD) by inducing the expression of gut barrier protective genes, and PHD have been identified as promising therapeutic targets in IBD.
PHD2 inhibition by ISM small molecule inhibitor stabilizes HIF-1α and drives intestial barrier protection

Insilico Medicine PHD — IBD Inhibitor Summary – IND-Enabling
Novel structure generated by AI
  • Distinctly different structure generated by Insilico Medicine's AI small molecule generation platform Chemistry42
Effective in both mono and combo therapies
  • Potent PHD enzymatic inhibition
  • Potent HIF-1α induction
  • Efficacious monotherapy in both TNBS and DSS colitis Model
  • Efficacious combo-therapy with anti-inflammatory drugs in both TNBS and DSS colitis model
Promising drug-ability as an oral agent
  • Good in vitro ADME profiles
  • Promising gut-restricted PK profiles across different preclinical animal species
Favorable safety margin
  • Promising MOS in rat and dog studies
  • Favorable in vitro safety profiles

Indication
Inflammatory bowel disease (IBD) is characterized by the inflammation of the colon and small intestine, leading to ulcerative colitis, and Crohn's disease. Ulcerative colitis primarily affects the colon and the rectum, whereas Crohn's disease affects the whole gastrointestinal tract. These diseases are characterized by chronic inflammation and wounding of the mucosa and loss of the intestinal epithelial barrier function.

Project Status – IND-Enabling
Insilico Medicine has developed a small molecule inhibitor, which is a potent gut restricted PHD inhibitor. This inhibition stabilizes HIF-1α and induces the expression of some intestinal barrier protection genes. Additionally, gut-restricted strategy offers an opportunity to deliver molecules to intestine with limited systematic exposure on-target effects associated with HIF-1α stabilization. This inhibitor demonstrated both monotherapy and combinational therapy efficacy in IBD mouse models.

PHD — CKD
Proline Hydroxylase (PHD) Inhibitors: Treatment of Anemic Chronic Kidney Disease (CKD) (IND-Enabling)
Assays Completed
Owned and Available for Licensing
In vivo efficacy studies with single agent
In vivo PK-PD
In vivo PK studies
In vitro ADME studies
Developability/CMC
In vitro cell-based
Toxicology studies
Enzymatic
Target Rationale
The hypoxia-inducible factors (the "HIF") are transcription factors that function as master regulators of oxygen homeostasis. When oxygen availability is limited, or during hypoxia, HIFs are stabilized to drive a transcriptional process by binding to hypoxia-responsive element (the "HRE") that promotes hypoxia adaptation. The final molecular step that controls HIFs stabilization converges on prolyl hydroxylases (the "PHDs").

Inhibition of PHD triggers erythropoiesis by inducing both renal and hepatic Erythropoietin (EPO) synthesis, which stimulates the production of red blood cells in the bone marrow and regulates the metabolism of iron, an indispensable component of functional red blood cells. Inhibition of PHD could also suppress the production of hepatic hepcidin, which has negative effects on iron mobilization. Inhibition of PHD might upregulate the expression of several iron metabolism genes. Thus, inhibition of PHD addresses both impaired EPO production and functional iron deficiency.
Overview of hypoxia-inducible factor (HIF) regulation of erythropoiesis
Kidney International Supplements (2021) 11, 8–25

Insilico Medicine PHD — CKD Inhibitor Summary – IND-Enabling
Novel structure generated by AI
  • Distinctly different structure generated by Insilico Medicine's AI small molecule generation platform Chemistry42
Effective in both mono and combo therapies
  • Potent PHD enzymatic inhibition
  • Potent HIF-1α induction
  • Potent EPO induction activity
  • Lower efficacious dose in CKD rats
  • Achieve target HGB level via lower EPO induction in CKD rats
Promising drug-ability as an oral agent
  • Good in vitro ADME profiles
  • Promising PK profiles across different preclinical animal species
  • No hits on KinomeScan and Cerep panels
Favorable
safety margin
  • Favorable in vitro safety profiles

Indication
Anemia of CKD is a form of normocytic normochromic, hyperproliferative anemia. The pathogenesis of anemia is impaired EPO production and functional iron deficiency. EPO is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia, in order to stimulate red blood cell production (erythropoiesis) in the bone marrow.

Widespread use of erythropoietin stimulating agents (ESA) improved overall quality of life and reduced the need for blood transfusions. Liberal administration of ESA was associated with increased risk of cardiovascular events, CKD progression, vascular access thrombosis, and overall mortality. Additional issues include, high cost of EPO analogs and associated resistance as well as side effects.

Alternatively, PHD inhibitors can be used to treat anemia by enhancing EPO secretion via upregulation of HIF-1α.

Project Status – IND-Enabling
Insilico Medicine nominated a potential best-in-class PHD inhibitor for anemia of CKD treatment that promotes erythropoiesis through both erythropoietin (EPO) induction and improved iron utilization. It is a small-molecule PHD inhibitor with novel scaffolds and distinct binding modes. In its functionality, it demonstrates a favorable safety profile both in vitro and in vivo studies.