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DISCOVERY AND DEVELOPMENT OF A MKK-4 INHIBITORS TO INCREASE LIVER REGENERATION

Abstract: Currently, the therapeutic options for treatment of liver failure are very limited. In an in vivo RNAi screen, mitogen-activated protein kinase kinase 4 (MKK4) has recently been identified as a major regulator in hepatocyte regeneration. By functional genetic silencing of MKK4. the target was validated in various experimental disease models. These data strongly supported the concept, that selective MKK4-inhibition with a          small molecule represents a promising and attractive approach for treatment of a complex and multi-factorial disease. Further to the observation that the approved BRAFV600E inhibitor vemurafenib shows a high affinity to  and moderate functional inhibition potency against MKK4, our hit optimization concept included classical interative SAR-optimization, but also a scaffold-hopping approach by changing the core heterocycle from 1H-pyrrolo[2,3-b]pyridine to 1H-pyrazolo[2,3-b]pyridine. Both approaches followed a mandatory multiparameter optimization. In vivo RNAi experiments also revealed, that MKK7 and JNK 1 are anti-targets and thereby defined the specification regarding the kinase selectivity. In both series, highly selective MKK4-inhibitors down to low nanomolar range with excellent selectivity profile against MKK7/JNK 1 could be achieved. LN3118 was identified as a tool compound with an IC50 value against MKK4 of 0.1 µM and an attractive selectivity profile and was used to validate MKK4 as a druggable target for treatment of liver disease. In experimental 2/3-hepatectomy in the mouse, orally administered LN3118 achieved a two-fold increase of hepatocyte proliferation. In acute CCl4-induced liver injury, cell death was prevented by 70%. Furthermore, LN3118 demonstrated therapeutic activity in two subchronic animal models. LN3118 reduced alcohol-induced steatosis and significantly reversed CCl4-induced liver fibrosis. The latest generation of compounds included highly potent MKK4-inhibitors with a pharmacological, toxicological and pharmacokinetic profile, which meet the specification of a clinical development candidate. Latest profiling and selection strategy for candidate selection will be presented.

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