PF-3758309 / Pfizer - LARVOL DELTA

Computational Identification of New Dual PAK4 and NAMPT Inhibitors. (PubMed, Int J Mol Sci) - "While existing inhibitors such as KPT9274 and PF-3758309 have demonstrated preclinical activity, their clinical translation has been limited by poor selectivity, suboptimal efficacy, and dose-limiting toxicities. Expanding the pool of dual inhibitors enhances opportunities for preclinical development, supports optimization of pharmacokinetic and safety profiles, and strengthens datasets for drug discovery. Collectively, this work broadens the landscape of dual PAK4 and NAMPT inhibitors and supports their potential application across multiple cancer types beyond triple-negative breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • NAMPT • PAK4

Targeting p21-activated kinase 4: Recent advances in the discovery of PAK4 inhibitors and strategies for isoform selectivity. (PubMed, Eur J Med Chem) - "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."

Journal • Review • Metabolic Disorders • Oncology • Targeted Protein Degradation • PAK4

Detergent selection as a determinant of protein melting behavior and drug-target interaction-calling in thermal stability proteomics. (PubMed, bioRxiv) - "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. 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."

Journal

PAK4 in the Tumor Immune Microenvironment: Biological Functions, Regulatory Mechanisms, and Targeted Therapeutic Strategies. (PubMed, Med Res Rev) - "Small-molecule PAK4 inhibitors (e.g., KPT-9274, PF-3758309, compound 55) and degraders (e.g., CPS-021) effectively suppress tumor growth in preclinical models. Elevated PAK4 expression correlates significantly with poor patient prognosis and resistance to immunotherapy, positioning it as both a predictive biomarker and a promising therapeutic target. Elucidating the PAK4-TME axis provides a mechanistic foundation for developing novel combinatorial strategies targeting the tumor microenvironment."

IO biomarker • Journal • Review • Metabolic Disorders • Oncology • HIF1A • PAK4

Targeting PAK1 suppresses tumor progression by promoting mRNA decay of oncogenic factors and enhancing chemotherapeutic efficacy in colorectal cancer. (PubMed, Genes Dis) - "Importantly, our results revealed that the PAK1 inhibitor, PF3758309, exhibited a profound synergistic effect with oxaliplatin in CRC. Collectively, our study unveils a novel function of PAK1 in CRC progression. Thus, these results highlight the potential of targeting PAK1 as a therapeutic strategy in CRC, particularly in combination with oxaliplatin."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CD44 • EIF4G1 • PAK1 • RPS6KB1 • SAA1

Higenamine Hydrochloride Attenuates Neuroinflammation in Type I Diabetic Mice by Inhibiting the CRTC2-CREB Signaling Pathway via PAK4. (PubMed, Mol Neurobiol) - "PF3758309 diminished the protective effects of HGN and elevated the serum levels of brain damage indicators (S100β and NSE) and inflammatory factors. HGN effectively reduces neuroinflammation and neurological dysfunction in T1D by targeting PAK4, suggesting its potential as a therapeutic agent for diabetes-related complications."

Journal • Preclinical • CNS Disorders • Diabetes • Immunology • Inflammation • Metabolic Disorders • Mood Disorders • Pain • Psychiatry • Type 1 Diabetes Mellitus • Vascular Neurology • IL1B • ITGAM • PAK4 • TNFA

Multi-omics analysis reveals RNA polymerase II degradation as a novel mechanism of PF-3758309's anti-tumor activity. (PubMed, Cell Death Discov) - "Furthermore, the small-molecule inhibitor MLN4924, which blocks NEDD8-activating enzyme, reversed the degradation of POLR2A/B/E, supporting the role of ubiquitin-proteasome pathways in this process. Functional assays confirmed that PF-3758309 inhibits tumor cell growth and migration by promoting ubiquitination-dependent degradation of POLR2A/B/E. These findings uncover a previously unrecognized mechanism of PF-3758309's anti-tumor activity and provide a basis for further investigation into its therapeutic potential."

Journal • Oncology • Targeted Protein Degradation • DDB2 • PAK4

The Potential Role of PAK4 in PDGF-BB-Mediated EMT and Metastatic Processes in Triple Negative Breast Cancer (EACR 2025) - "Consequently, the PDGF-BB/PDGFR/PAK4 axis can be considered a significant therapeutic target in the management of cancer progression."

Metastases • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDH1 • CDH2 • PAK4 • VIM

Endothelial Heg1 promotes liver sinusoidal endothelial cells capillarization to aggravate liver fibrosis (EASL 2025) - "Inhibition of PAK4 by PF-3758309 reversed LSEC capillarization triggered by Heg1 overexpression... In conclusion, our results demonstrate that Heg1 promotes liver fibrosis by inducing LSECs capillarization, underscoring Heg1 as a promising druggable target for liver fibrosis treatment."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • HEG1 • PAK4

Phosphoproteomics identifies determinants of PAK inhibitor sensitivity in leukaemia cells. (PubMed, Cell Commun Signal) - "In summary, our data define the proteomic, molecular and functional responses of primary and immortalised AML cells to PF-3758309 and suggest a route to personalise AML treatments based on PAK inhibitors."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AMPK • FLT3 • MYC • PRKCA • STAT5

Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities. (PubMed, Bioorg Med Chem) - "Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors."

Journal • Review • Oncology

A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction. (PubMed, Adv Sci (Weinh)) - "Genetic loss-of-function experiments showed that AMPK limits the induction of ferroptosis, and consequently, PF-3758309 treatment restores the sensitivity toward ferroptosis inducers. The work established a chemical scaffold for the development of specific AMPK-targeting compounds and deciphered the framework for the development of AMPK inhibitor-based combination therapies tailored for PDAC."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • AMPK

The Efficacy of PAK4 Inhibition to Block Visfatin-Induced Liver Cancer Progression (EACR-AACR 2024) - "Hepa1-6 and SNU-449 liver cancer cells were analyzed under the following conditions: serum free media (SFM), fetal bovine serum (FBS), SFM + visfatin (40 ng/mL), SFM + visfatin + PF-3758309 (1 nM), and SFM + PF...Conclusion We show that visfatin activates PAK4, which is the first step in our proposed mechanism. We will continue to look at the downstream effects of visfatin activation and PF in liver cancer cells and mouse liver and tumor tissue and serum."

Clinical • Gastrointestinal Cancer • Genetic Disorders • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • Oncology • Solid Tumor • NAMPT

Simultaneous inhibition of PI3K and PAK in preclinical models of neurofibromatosis type 2-related schwannomatosis. (PubMed, Oncogene) - "We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis."

Journal • Preclinical • Brain Cancer • Fibrosis • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • NF2

Design, synthesis and anticancer activity evaluation of 4-(3-1H-indazolyl)amino quinazoline derivatives as PAK4 inhibitors. (PubMed, Bioorg Med Chem) - "Subsequent cellular assay demonstrated that compound 27e possessed the strongest antiproliferative activity against A549 cells with an IC value of 0.61 μM, a little bit better than PF-3758309...A docking model between compound 27e and PAK4 was proposed to elucidate its possible binding modes. As a promising PAK4 inhibitor, compound 27e may serve as a candidate for the development of novel PAK4-targeted anticancer drug."

Journal • Oncology

Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma. (PubMed, Blood Sci) - "PAK inhibitors, PF3758309 (PF) and FRAX597, could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition. These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin. Collectively, our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1 • PAK2

PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry. (PubMed, Int J Biol Sci) - "In vivo, both CSF2 silencing and PF3758309 suppressed PAK1-driven tumor proliferation and angiogenesis. Conclusively, the nuclear entry of overexpressed/activated PAK1 endows myxofibrosarcomas with pro-angiogenic function, highlighting the vulnerable PAK1/STAT5B/CSF2 regulatory axis."

Journal • Oncology • Sarcoma • Solid Tumor • CSF2 • MVD • PAK1 • PAK2 • STAT5B

Combined blockade of mTOR and p21-activated kinases pathways prevents tumour growth in KRAS-mutated colorectal cancer. (PubMed, Br J Cancer) - "In conclusion, our results suggest the simultaneous blockade of mTOR and Pak pathways as a promising alternative therapeutic strategy for patients affected by KRAS-mut colorectal cancer."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer. (PubMed, NPJ Breast Cancer) - "Finally, treatment with Pak1 inhibitors, PF-3758309 (PF309) and NVS-PAK1-1, restored cell sensitivity to fulvestrant and abemaciclib of MCF7-FAR and T47D-FAR cells, both in vitro and in vivo. In conclusion, our data suggested a pivotal role for Pak1 in resistance to ET and CDK4/6i in ER+ breast cancers. These data might promote the rationale for the development of novel Pak1 inhibitors for treatment of patients with ER+ BC progressing on ET plus CDK4/6i."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • PAK1

Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Eµ-Myc lymphoma cells. (PubMed, Biochem J) - "Moreover, treatment with the PI3K inhibitor Pictilisib (GDC-0941) selectively inhibited the growth of reimplanted c-Rel-/- and RelAT505A, but not wild type (WT) Eµ-Myc lymphomas...Here, the PAK inhibitor, PF-3758309 successfully overcame resistance of RelAT505A but not WT lymphomas. These findings demonstrate that up-regulation of multiple bypass pathways occurs in CHK1 inhibitor resistant Eµ-Myc lymphomas. Consequently, drugs targeting these pathways could potentially be used as either second line or combinatorial therapies to aid the successful clinical application of CHK1 inhibitors."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Combination of PAKs inhibitors IPA-3 and PF-3758309 effectively suppresses colon carcinoma cell growth by perturbing DNA damage response. (PubMed, Int J Radiat Biol) - "Additionally, this combination sensitized colon cancer cells to ionizing radiation that resulted in inhibition of cell growth. Significance: Collectively, our findings show for the first time that cotreatment of IPA-3 with PF-3758309 exhibits superior inhibitory effects on colon carcinoma cell growth via inducing DNA damage-related cell death and also enforces a cell cycle arrest."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CDC42 • CDKN1A

Anti-tumor activity of KRASG12C inhibitors is enhanced when combined with Cdc42 effector p21-activated kinase 4 targeting agents (AACR 2022) - "In this study, we rationally targeted two parallel signaling pathways by combining KRASG12C inhibitors with the PAK4 inhibitor KPT-9274 in KRASG12C mutant PDAC and NSCLC in vitro and in vivo models. We evaluated the cytotoxicity and molecular profile of KRASG12C inhibitors in combination with PAK4 inhibitor KPT-9274 as well as positive control PF-3758309 in KRASG12C mutant 2D and 3D cellular/spheroid models...Tumor volumes were assessed throughout the treatment period using an ultrasound scanner. PAK4 inhibitor KPT-9274 synergized with both sotorasib and adagrasib yielding suppressed growth of KRASG12C mutant PDAC and NSCLC cells in 2D and 3D cultures, but not in KRASwt, KRASG12V, and KRASG12D cell lines (NCI RASless MEFs)... This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitors. This combination can simultaneously target direct KRAS downstream effectors and the parallel PI3K/AKT oncogenic signaling warranting further clinical..."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDC42 • KRAS • PAK4

PAK4 inhibition improves PD1 blockade immunotherapy in prostate cancer (AACR 2022) - "PAK4 inhibitors PF-3758309 (PF) and KPT-9274 (KPT) were evaluated in murine models. A combination of KPT and αPD1 significantly reduced tumor growth when compared to WT (P<.01) and WT αPD1 (P<.01). In conclusion, PAK4 inhibition increased immune infiltration and improved αPD1 treatment response in preclinical mouse prostate cancer models."

IO biomarker • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • IFNG • NAMPT • PD-L1

The Combined Use of Orf Virus and PAK4 Inhibitor Exerts Anti-tumor Effect in Breast Cancer. (PubMed, Front Microbiol) - "PF-3758309 is a potent PAK4-targeted inhibitor...In summary, we have clarified the oncolytic effect of ORFV on breast cancer, and found that the combination of ORFV and PAK4 inhibitor can effectively improve the oncolytic effect of ORFV. We hope our research could provide a new idea for the development of new treatment strategies for breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor

In Situ Imaging of Formaldehyde in Live Mice with High Spatiotemporal Resolution Reveals Aldehyde Dehydrogenase-2 as a Potential Target for Alzheimer's Disease Treatment. (PubMed, Anal Chem) - "Activating ALDH2 with the small molecular activator Alda1 significantly protected neurovascular cells from formaldehyde overload and consequently from impairment during AD progress both in vitro and in vivo. These findings revealed PFM309 as a robust tool to study AD pathology and highlight ALDH2 as a potential target for AD drug development."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Immunology • ALDH2