FIBROKINASE INHIBITOR PROGRAM
ANG-3070 - Fibrokinase Inhibitor Program
ANG-3070 is an orally bioavailable small molecule fibrokinase inhibitor in advanced preclinical development for treatment of chronic kidney disease and polycystic kidney disease.
We discovered a class of novel kinase inhibitors that targets several cellular receptors involved in fibrosis that scars and damages organs including the kidney. Our most advanced candidate is ANG-3070, an orally bioavailable small molecule, which has shown efficacy in preclinical renal fibrosis models both alone and in combination with current standard-of-care therapy. ANG-3070 also has shown anti-fibrotic activity in fibrocystic kidney and liver disease as well as NASH with advanced fibrosis.
CYP INHIBITORS PLATFORM
ANG-3586 CYP11B2 Aldosterone Synthase Inhibitor
ANG-3563 CYP11B1 Inhibitor / Cortisol Synthesis Inhibitor
Through molecular modeling and rational drug design, we have built a proprietary platform to create highly specific libraries of inhibitors of cytochrome P450 (“CYP”) enzymes. The cytochrome P450 family of proteins includes enzymes responsible for the metabolism of drugs and ingested toxic substances and enzymes responsible for the metabolism of endogenous substances such as steroids, vitamins and lipids. We have modified and tailored our compounds for selectivity to inhibit specific enzymes. By thus modulating the activity of specific endogenous signal transduction pathways, we have the opportunity to target different diseases in which those pathways are implicated.
Our most advanced CYP inhibitor program is targeted towards aldosterone synthase (CYP11B2), with inhibitors being evaluated as a potential treatment for chronic kidney disease and hypertension. Compound ANG3586 is selective for aldosterone synthase (over the closely related enzyme CYP11B1) and has shown activity in preclinical animal models of chronic kidney disease and polycystic kidney disease. More selective compounds have been identified and are undergoing IND-enabling studies.
As a product of Angion’s proprietary CYP inhibitor platform, we have also identified compounds that predominantly inhibit CYP11B1 as cortisol lowering agents for potential use in Cushing’s syndrome patients.
Another Angion CYP inhibitor targets retinoic acid hydroxylase, encoded by the CYP26 genes. This CYP is responsible for metabolizing retinoic acid, an endogenous molecule with beneficial activities in many diseases as well as in maintaining the integrity of skin. Retinoic acid is present in some anti-wrinkle creams, but it has toxic side effects. By inhibiting CYP26 in the skin, the body’s endogenous levels of retinoic acid can be elevated to benefit the skin without the side effects of applied retinoic acid. Angion licensed the rights to one CYP26 inhibitor, ANG3522, to a privately-held dermatology company for use in dermatological indications, in both cosmetic and prescription products.
ANG 4102 – ASK1 Inhibitor
Apoptosis signal-regulating kinase 1 (ASK1) is a member of MAP kinase kinase kinase (MAP3K) family of protein kinases. In response to cellular stress, such as oxidative stress, it stimulates signal transduction pathways resulting in the activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. ASK1 has been found to be involved in several diseases, such as neurodegenerative diseases, diabetes and cardiovascular diseases.
In contrast to p38 and JNK, which have important homeostatic roles, ASK1 is thought to be only activated in pathologic states, thus making it an attractive target to specifically interfere with pathologic, but not homeostatic signaling through the p38 MAPK and JNK signal transduction pathways. Angion has identified a promising proprietary lead series of potent small molecule ASK1 inhibitors, exemplified by ANG4102, and is evaluating their potential use in Acute Kidney Injury and Myocardial Infarction.
ANG 4201 - ROCK2 Inhibitor
The Rho kinase family members, consisting of Rho-associated kinase1 (ROCK1) and ROCK2, are serine–threonine kinases that are activated by Rho GTPases. We have confirmed the upregulation of ROCK2 in animals models of renal disease which is associated with increases in renal collagen, hydroxyproline and alpha-SMA, markers of renal fibrosis.
We are employing state of the art core-hopping method and structure-based drug design to develop orally bioavailable and highly selective ROCK2 versus ROCK1 inhibitors for the treatment of renal fibrosis. We have identified ANG 4201 as our lead candidate which is a selective for ROCK2 and has shown promising antifibrotic effects in preclinical animal models of kidney disease. We believe that our selective ROCK2 inhibitor will not only prove efficacious in mitigating fibrosis but will also carry a lower risk of side effects associated with chronic dosing.