NVS-PAK1-1
目录号 : GC32830An allosteric inhibitor of PAK1
Cas No.:1783816-74-9
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >99.00%
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- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Inhibition of PAK1 kinase activity is measured using the Caliper assay. The assay is performed using 384-well microtiter plates. Compounds (NVS-PAK1-1) are tested as 8-point dose responses. The assays are prepared by addition of 50 nL of compound solution in 90% DMSO directly into the empty plate. Subsequently, 4.5 µL of the enzyme solution is added to each well and the resulting solution is pre-incubated at 30°C for 60 min, followed by addition of 4.5 µL of the peptide/ATP-solution. After 60 min incubation at 30°C, reactions are terminated by addition of 16 μL per well of the stop solution. Plates with terminated kinase reactions are transferred to the Caliper LC3000 workstations for reading. Product formation is measured in a microfluidic mobility shift assay. IC50 values are derived from percent inhibition values at different compound concentrations by non-linear regression analysis[1]. |
References: [1]. Karpov AS, et al. Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor. ACS Med Chem Lett. 2015 May 22;6(7):776-81. |
NVS-PAK1-1 is an allosteric inhibitor of p21-activated kinase 1 (PAK1), a non-receptor serine/threonine kinase involved in tumorigenesis (Kd = 7 nM).1 It has an IC50 value of 5.2 nM in a PAK1 dephosphorylation assay. NVS-PAK1-1 is selective for PAK1 over PAK2 (Kd = 400 nM) and over a panel of 442 kinases, where it did not inhibit any other kinases by greater than 80%.1,2 It inhibits phosphorylation of MEK Ser289 when used at concentrations ranging from 6 to 20 ?M but does not inhibit proliferation of Su86.86 cells at concentrations lower than 2 ?M.1 See the Structural Genomics Consortium (SGC) website for more information.
1.Karpov, A.S., Amiri, P., Bellamacina, C., et al.Optimization of a dibenzodiazepine hit to a potent and selective allosteric PAK1 inhibitorACS Med. Chem. Lett.6(7)776-781(2015) 2.Semenova, G., and Chernoff, J.Targeting PAK1Biochem. Soc. Trans.45(1)79-88(2017)
Cas No. | 1783816-74-9 | SDF | |
Canonical SMILES | FC1=CC2=C(C=C1)N(CC(F)F)C3=C(C=C(Cl)C=C3)C(N[C@H]4CCN(C(NC(C)C)=O)C4)=N2 | ||
分子式 | C23H25ClF3N5O | 分子量 | 479.93 |
溶解度 | DMSO : ≥ 125 mg/mL (260.45 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.0836 mL | 10.4182 mL | 20.8364 mL |
5 mM | 0.4167 mL | 2.0836 mL | 4.1673 mL |
10 mM | 0.2084 mL | 1.0418 mL | 2.0836 mL |
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Development and Utility of a PAK1-Selective Degrader
J Med Chem 2022 Dec 8;65(23):15627-15641.PMID:PMC10029980DOI:10.1021/acs.jmedchem.2c00756.
Overexpression of PAK1, a druggable kinase, is common in several malignancies, and inhibition of PAK1 by small molecules has been shown to impede the growth and survival of such cells. Potent inhibitors of PAKs 1-3 have been described, but clinical development has been hindered by recent findings that PAK2 function is required for normal cardiovascular function in adult mice. A unique allosteric PAK1-selective inhibitor, NVS-PAK1-1, provides a potential path forward, but has modest potency. Here, we report the development of BJG-05-039, a PAK1-selective degrader consisting of NVS-PAK1-1 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon. BJG-05-039 induced selective degradation of PAK1 and displayed enhanced anti-proliferative effects relative to its parent compound in PAK1-dependent, but not PAK2-dependent, cell lines. Our findings suggest that selective PAK1 degradation may confer more potent pharmacological effects compared with catalytic inhibition and highlight the potential advantages of PAK1-targeted degradation.
PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2)
Hum Mol Genet 2021 Aug 12;30(17):1607-1617.PMID:34075397DOI:10.1093/hmg/ddab106.
Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.