DISCOVERY<\/b> <\/b>AND DEVELOPMENT OF A MKK-4 INHIBITORS TO<\/b> <\/b>INCREASE<\/b> <\/b>LIVER<\/b> <\/b>REGENERATION<\/b><\/p>\n
Abstract:<\/b> 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.<\/b> <\/b>the target was validated in various experimental disease models. These data strongly supported the concept, that selective MKK4-inhibition with a\u00a0<\/span> \u00a0 \u00a0 \u00a0 \u00a0 <\/span>small molecule represents a promising and attractive approach for treatment of a complex and multi-factorial disease. Further to the observation that the approved BRAF<\/b>V600E <\/sup><\/b>inhibitor vemurafenib shows a high affinity to\u00a0<\/span> 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<\/i>-pyrrolo[2,3-b<\/i>]pyridine to 1H<\/i>-pyrazolo[2,3-b<\/i>]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<\/sub> value against MKK4 of 0.1 \u00b5M 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<\/sub>-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.<\/p>\n","protected":false},"excerpt":{"rendered":" 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…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"post_series":[],"class_list":["post-478","post","type-post","status-publish","format-standard","hentry","category-sem-categoria","entry","no-media"],"_links":{"self":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/478","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/comments?post=478"}],"version-history":[{"count":2,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/478\/revisions"}],"predecessor-version":[{"id":480,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/posts\/478\/revisions\/480"}],"wp:attachment":[{"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/media?parent=478"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/categories?post=478"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/tags?post=478"},{"taxonomy":"post_series","embeddable":true,"href":"https:\/\/brazmedchem.org\/2022\/wp-json\/wp\/v2\/post_series?post=478"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}