PF-03758309 PAK4 inhibitor
- Known as:
- PF-03758309 PAK4 suppressor
- Catalog number:
- a-1091
- Product Quantity:
- USD
- Category:
- -
- Supplier:
- ActivBio Active Biochem
- Gene target:
- PF-03758309 PAK4 inhibitor
Related genes to: PF-03758309 PAK4 inhibitor
- Gene:
- PAK4 NIH gene
- Name:
- p21 (RAC1) activated kinase 4
- Previous symbol:
- -
- Synonyms:
- -
- Chromosome:
- 19q13.2
- Locus Type:
- gene with protein product
- Date approved:
- 2001-07-12
- Date modifiied:
- 2016-05-03
Related products to: PF-03758309 PAK4 inhibitor
Related articles to: PF-03758309 PAK4 inhibitor
- Environmental chemicals may suppress sperm motility (SM), hyperactivation, and capacitation, thus contributing to male infertility. This investigation was designed to examine the impacts of thiram on human SM and capacitation. - Source: PubMed
Publication date: 2026/06/27
Wen ZinaQiu QinghongDuan LiLiu GangWang YiyanTian ErpoGe Ren-Shan - p21-activated kinase 4 (PAK4), a Group II PAK family member, is a therapeutically relevant candidate target in cancer, metabolic disease, and tissue injury. However, translation of PAK4 biology into drug candidates has been constrained by the conserved ATP-binding architecture of PAK isoforms, unfavorable pharmacokinetic profiles, and suboptimal clinical efficacy. We summarize the evolution of ATP-competitive Type I inhibitors, Type I½ back-pocket inhibitors, allosteric modulators, and PROTAC degraders, and compare representative compounds using potency, isoform selectivity, cellular activity, oral bioavailability, and development status. Particular emphasis is placed on structural determinants of selectivity, including the αC-helix-dependent hydrophobic back pocket, the inward Asp444/Asp458 floor pocket arrangement, and peripheral microenvironment differences that distinguish PAK4 from Group I PAKs. We also summarize the potential ADMET liabilities-such as pronounced efflux, metabolic instability, and poor oral bioavailability-that may arise from structural modifications aimed at enhancing PAK4 selectivity, and discuss rational optimization strategies to navigate these inherent barriers. Finally, we discuss clinical lessons from PF-3758309 and KPT-9274/padnarsertib and highlight how allosteric inhibitors and PROTAC degraders may help address limitations of conventional ATP-site inhibitors. - Source: PubMed
Publication date: 2026/07/31
Shi RuiqingFeng XueWang ZixuanXing YongshuaiYan XianjunXing RuijuanZhang Guogang - Thermal proteome profiling (TPP) and proteome integral solubility alteration (PISA) assays measure drug-target interactions by monitoring protein thermal stability across the proteome. While detergents are routinely used in lysate-based thermal profiling, the field lacks consensus on whether detergents should be present during the melting step or only added afterward as an extraction buffer, and whether detergent identity matters for this choice. Here, we evaluate how commonly used detergents and the timing of their use in thermal stability workflows affect proteome-wide thermal stability and PISA hit calling in TF-1 lysates. We find that NP-40 and DDM produce highly correlated melting profiles when used exclusively as post-melt extraction buffers, but diverge substantially when present during the melting step. DDM in particular prevents the thermally-induced loss in solubility of large classes of proteins, such as cell surface proteins, and these effects propagate directly into PISA hit calling. Performing the PISA melt in DDM versus NP-40 results in the gain and loss of distinct drug-target interactions for both the PAK4 inhibitor PF-3758309 and the PLK1 inhibitor volasertib. Notably, DDM enables detection of a volasertib-TMEM97 interaction that was previously not detected in NP-40. However, we also find that the stabilization effects of DDM mask the identification of some known PISA hits for these drugs. We further introduce a four-parameter logistic model of protein melting to aid in modeling of these findings and a linear regression framework for PISA hit calling that outperforms pairwise t-tests in low-replicate settings. Together, these results establish detergent selection as a tunable experimental variable in thermal profiling and suggest that some drug-target engagements previously attributed exclusively to intact-cell context may be recoverable in lysates with appropriate buffer conditions. - Source: PubMed
Publication date: 2026/07/24
Sniezek CatherineGlukhova Veronika ASchmitz ChristianVlajic KatarinaSchweppe Devin K - Understanding the molecular mechanisms that govern hepatic stellate cell (HSC) fate is essential for developing effective antifibrotic therapies. Yes-associated protein (YAP) plays a pivotal role in organ fibrogenesis and HSC activation, but its upstream regulatory signals in liver fibrosis remain largely unknown. Here, we demonstrate the role of p21-activated kinase 4 (PAK4), an emerging therapeutic target, in the activating phosphorylation of YAP and subsequent HSC activation. PAK4 expression was markedly upregulated in activated HSCs from patients and mice with liver fibrosis and correlated with disease severity. Silencing PAK4 suppressed hallmark features of HSC activation, including fibrotic activity, proliferation, migration, and contractility. HSC-specific deletion of Pak4 and oral administration of a selective PAK4 inhibitor attenuated hepatic fibrosis in mice. Mechanistically, PAK4 directly phosphorylated YAP at T428, a previously unrecognized site, leading to YAP stabilization, nuclear accumulation, and transcriptional activation, which in turn promoted HSC activation. Overexpression of a phospho-inactive YAP mutant in HSCs reduced fibrogenesis, validating the functional importance of PAK4-mediated YAP phosphorylation. Notably, T428-phosphorylated YAP levels were substantially elevated in livers from patients with fibrosis. Our findings reveal a new PAK4-YAP signaling axis in HSCs, whereby PAK4-mediated T428 phosphorylation of YAP promotes its activation and drives liver fibrosis. These insights highlight a potential therapeutic strategy targeting HSC activation. - Source: PubMed
Publication date: 2026/07/30
Kim Gil-HwanRho HyunsooLee Chang HunHong You-JungPark YongdoYu Hwang ChanSong Mi-YoungJo Hye JinKang Eun JooHan RiYu Song YiSeki EkihiroLee YoonjiLee SangkyuBae Eun JuPark Byung-HyunHan Chang Yeob - : Docetaxel is a frontline chemotherapeutic agent for breast cancer; however, therapeutic resistance remains a major clinical challenge. Emerging evidence suggests that chemotherapy-induced adaptive phosphorylation events can promote survival signaling and contribute to drug resistance. However, the phosphoproteomic mechanisms underlying docetaxel-induced adaptive responses remain poorly characterized. : We performed integrated quantitative proteomic and phosphoproteomic profiling in breast cancer cells following docetaxel exposure. Candidate kinases associated with phosphorylation remodeling were identified and validated using TCGA-BRCA and CPTAC clinical datasets. The functional significance of PAK4 phosphorylation was validated using phosphomimetic and phospho-deficient mutants, pharmacological inhibition, and assessment of microtubule stabilization. : Integrated phosphoproteomic analysis revealed extensive phosphorylation remodeling following docetaxel treatment and identified PAK4 as a candidate kinase associated with the adaptive response. Analysis of the CPTAC phosphoproteomic dataset showed that phosphorylation of PAK4 at S474 was elevated in breast cancer tissues, increased with tumor stage, and was associated with poorer overall survival. In breast cancer cells, docetaxel induced phosphorylation of PAK4 at S474 without altering total PAK4 expression. Functionally, phosphomimetic PAK4 (S474D) reduced docetaxel sensitivity, whereas phospho-deficient PAK4 (S474A) enhanced drug sensitivity. Pharmacological inhibition of PAK4 using LCH-7749944 significantly enhanced the inhibitory effect of docetaxel on cell viability and increased apoptosis in breast cancer cells. Mechanistically, PAK4 inhibition enhanced docetaxel-induced microtubule stabilization, as evidenced by increased α-tubulin acetylation and accumulation of stabilized microtubule structures. : Our study demonstrates that docetaxel induces global phosphorylation network reprogramming in breast cancer cells and identifies PAK4 S474 phosphorylation as a key determinant of docetaxel sensitivity. Inhibition of PAK4 enhances microtubule stabilization and improves the efficacy of docetaxel, providing a potential combinatorial strategy to overcome taxane resistance. - Source: PubMed
Publication date: 2026/07/20
Liu ShiyangLi ShuyuLu ZonghongTong XiaofeiGui ZhengweiSun MeinaZhang Lin