The Science

KMO Inhibition

A first-in-class therapeutic approach with a strong rationale in acute and chronic inflammation

Kynurenine monooxygenase (KMO) is an enzyme localized to mitochondria inside cells that acts at a key point in the kynurenine pathway of tryptophan metabolism. KMO converts kynurenine into 3-hydroxykynurenine (3HK). Excess 3HK production is implicated in tissue damage and dysregulation of the immune system during inflammation.

OPTIMIZED KMO INHIBITORS MOVED INTO DEVELOPMENT

Kynos’ proprietary small molecule KMO inhibitors result from an extensive optimization program (Nature Comms 2017 and J Med Chem 2017), are highly potent and selective and demonstrate excellent properties for further development.

Kynos’ lead molecule, KNS366, is in Phase I clinical development.​

KMO inhibition in acute inflammation

Acute pancreatitis and acute kidney injury

KMO is an important therapeutic target for multiple organ dysfunction, particularly that triggered by acute pancreatitis and the systemic inflammatory response. Kynos’ KMO inhibitors are protective against secondary organ damage in experimental systemic inflammation triggered by severe acute pancreatitis (Nature Medicine 2016)​

KMO enzyme is highly expressed in kidney tubular epithelial cells, and the KMO product 3HK is toxic to these cells in laboratory experiments. Mice without functioning KMO made by gene knockout are protected from ischemic reperfusion injury. ​

Kynos’ lead KMO inhibitor protects against kidney injury in acute pancreatitis models and in a sophisticated model of kidney reperfusion injury associated with cardiopulmonary bypass surgery​.

COMPELLING RATIONALE IN INDICATIONS WITH HIGH UNMET MEDICAL NEED

Acute pancreatitis and acute kidney injury are major unmet medical needs which have no therapeutics specifically approved in the US or Europe to treat either indication​.

KMO inhibition in chronic
immuno-inflammatory disorders​

KMO is highly expressed in immune cells (particularly plasmacytoid dendritic cells, B lymphocytes, and monocyte/macrophages) as well as in liver and kidney tissue. KMO has been implicated in chronic diseases where inflammation and immunity intersect.​

KYNURENINE PATHWAY DYSREGULATION IN CHRONIC IMMUNO-INFLAMMATION

Kynos is actively investigating the therapeutic potential of KMO inhibition in several chronic disease settings, specifically at the interface of inflammation and immunity where excess KMO activity has been identified.

One example of this is endometriosis. KMO is highly expressed in cycling endometrium and in pathological cystic gland structures in human endometriosis. Therapeutic blockade using Kynos KMO inhibitors has shown reduced disease burden and improvement of symptoms in a preclinical experimental model of endometriosis.