The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacological properties by structure–activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metabolism and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good solubility, good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.
The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity, and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (> 400-fold), potent inhibition of cofilin phosphorylation in A7r5,PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥ 80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.
Both JNK and LRRK2 are associated with Parkinson's disease (PD). Here we report a reasonably selective and potent kinase inhibitor (compound 6) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC 50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. 6 also exhibited good cell potency, inhibited LRRK2:G2019S induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families. Design of such a probe molecule may help enable testing if dual JNK and LRRK2 inhibitions have added or synergistic efficacy in protecting against neurodegeneration in PD. KeywordsDual Inhibitor; Bidentate-Binding kinase inhibitors; JNK3; LRRK2; Parkinson's Disease; PD The design and identification of potent and highly selective JNK inhibitors has been avidly pursued in the past few years due to potential wide spread therapeutic applications. [1][2][3][4] In particular, development of brain penetrant small molecule inhibitors for JNK and LRRK2 has been a major focus in order to develop efficacious therapeutics for Parkinson's disease (PD) 2, 3, 5-10 and other neurodegenerative diseases for JNK, such as Alzheimer's (AD) 11 , Huntington's disease (HD) 12 , amyotrophic lateral sclerosis (ALS) 13 and multiple sclerosis (MS). 14 To this end, our lab and the Elan group have successfully developed selective, brain penetrant, and orally bioavailable small molecule JNK inhibitors 2,3,[15][16][17][18][19] which showed good efficacy for the treatment of neurodegeneration models in particular and PD animal models specifically (such as SR3306 developed in our labs). LRRK2 inhibitors have also been discovered in several labs, 5, 7 however the selectivity, cell potency, and especially the brain penetration capability for these initial compounds still need improvement. Recent To extend our work in developing novel neuroprotective therapeutics for PD, we set out to discover unique JNK inhibitors from diversified scaffolds. It was our goal to develop compounds that were capable of inhibiting both JNK3 and LRRK2 simultaneously (dual inhibitors) in the hope that these compounds would exhibit greater efficacy than compounds that inhibited only JNK or LRRK2 individually. Dual inhibitors can be used as in vitro or in vivo probes to test the hypothesis that dual inhibition of JNK and LRRK2 may be additive or synergistic in the treatment of both familial and idiopathic PD. A dual inhibitor is preferred over combined, individual JNK and LRRK2 inhibitors because it eliminates complications of drug-drug interactions and the need to optimize individual inhibitor doses for efficacy.The major challenge in developing kinase inhibitors is to gain high selectivity in order to dimi...
Three JNK isoforms, JNK1, JNK2, and JNK3 have been reported and unique biological function has been ascribed to each. It is unknown if selective inhibition of these isoforms would confer therapeutic or safety benefit. To probe JNK isoform function we designed JNK2/3 inhibitors that have >30-fold selectivity over JNK1. Utilizing site-directed mutagenesis and x-ray crystallography we identified L144 in JNK3 as a key residue for selectivity. To test whether JNK2/3 selective inhibitors protect human dopaminergic neurons against neurotoxin-induced mitochondrial dysfunction, we monitored reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP). The results showed that JNK2/3 selective inhibitors protected against 6-hydroxydopamine-induced ROS generation and MMP depolarization. These results suggest that it was possible to develop JNK2/3 selective inhibitors and that residues in hydrophobic pocket I were responsible for selectivity. Moreover, the findings also suggest that inhibition of JNK2/3 likely contributed to protecting mitochondrial function and prevented ultimate cell death.
One is not like the other: The title approach proceeds by stepwise coupling of three relatively simple substrates. Three natural product‐inspired agents are described, one of which has natural product‐like toxicity for HeLa and MCF7 cells. It is isoform‐selective, thus targeting Hsp90α/β over Grp94, and adopts a conformation similar to that of geldanamycin when complexed with Hsp90.
A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure−activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC 50 = 15 nM), had high selectivity against p38 (IC 50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 Å. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition. A s a member of the mitogen-activated protein kinase (MAPK) family, the c-Jun N-terminal kinases (JNKs) are activated (dual phosphorylation on threonine and tyrosine) via an upstream kinase signaling cascade initiated by environmental stress and culminate in effects on both nuclear and mitochondrial function. 1−3 It is well-known that there are three human JNK isoforms, JNK1, JNK2, and JNK3. 4 JNK1 and JNK2 are ubiquitously expressed in a variety of human tissues. 2,5 Recent studies showed that JNK1 and JNK2 play an important role in the development of diabetes, obesity, arthritis, cancer, and heart disease. JNK1 seems to be involved in the development of obesity induced insulin resistance, which implies inhibition of JNK1 might be an effective way of treating type-2 diabetes. 6,7 JNK2 has been implicated to play an important role in many autoimmune disorders such as rheumatoid arthritis, asthma, and cancer, as well as in a broad range of diseases with an inflammatory component. 5,8 JNK3 is primarily expressed in the central nervous system (CNS) and plays an important role in Alzheimer's disease, 9 Parkinson's disease, and stroke. 3,10,11 Therefore, JNK inhibitors may have implications in many therapeutic areas, and development of JNK inhibitors as therapeutic agents has gained considerable interest over the past few years. 12−17 Given the significant amount of evidence supporting the role of JNK3 in neurodegenerative disorders, our interest is in discovering potent, selective JNK3 inhibitors with good in vivo pharmacokinetics (PK) profiles as potential therapeutics for CNS disease. 3,10,11,18−20 The pyridopyrimidinone scaffold based compound 1 (Figure 1) was identified in our preliminary medicinal chemistry efforts as an ATP competitive pan-JNK inhibitor with an IC 50 of 58 nM against JNK3 and 18 nM over both JNK1 and JNK2. This scaffold (pyridopyrimidinone) has long been shown to be good for kinase inhibition. 21 While genetic evidence suggests that JNK1 inhibition is not required for efficacy in many CNS applications, the...
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