FRAX597 / Afraxis, Roche, Scripps Research Institute - LARVOL DELTA

The Splicing-Associated Network PAK1-Clk-SRRM1 Is a Critical Vulnerability to Overcome Chemoresistance in Acute Myeloid Leukemia (ASH 2023) - "To address this issue, we generated an MLL-AF9-driven syngeneic mouse model of AML, which we evolved to develop resistance to a front-line chemotherapy regimen by repetitive exposure to a maximally-tolerated combination of cytarabine and doxorubicin...Human and murine chemoresistant cells were found to be markedly more sensitive to inhibitors of PAKs (FRAX597) and CLKs (TG003 and ML167) compared to their naive counterparts, an effect which was even further enhanced by treatment with cytarabine and daunorubicin...In conclusion, our study advances the rationale that combined inhibition of PAK1 and CLK kinases effectively curtails malignant cell splicing adaptation to chemotherapy by affecting SRRM1 function. Combined PAK1 and CLK inhibitors either concomitant with or sequential to chemotherapy may offer greater clinical benefit and significantly improve AML patients' long-term outcomes."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • PRPF8

Chinese Family With Knobloch Syndrome Associated With a Novel PAK2 Variant Leading to Reduced Phosphorylation Levels. (PubMed, Mol Genet Genomic Med) - "The clinical manifestations in this patient may be associated with a novel PAK2 variant, and the atypical presentation of KNO suggests that PAK2-related KNO may have a broader phenotypic spectrum."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • COL18A1 • PAK2

Polymeric nanofiber leveraged co-delivery of anti-stromal PAK1 inhibitor and paclitaxel enhances therapeutic effects in stroma-rich 3D spheroid models. (PubMed, Int J Pharm) - "In this study, we propose to develop a dual delivery approach by combining p21-activated kinase 1 (PAK1) inhibitor (FRAX597) to inhibit tumor stroma and chemotherapeutic agent paclitaxel (PTX) to kill cancer cells using electrospun nanofibers. Overall, this study provides a new therapeutic strategy to inhibit the tumor stroma using PAK1 inhibitor and thereby enhance the efficacy of chemotherapy using nanofibers as a local delivery system for unresectable or residual tumor. Use of 3D models to evaluate nanofibers highlights these models as advanced in vitro tools to study the effect of controlled release local drug delivery systems before animal studies."

Journal • Stroma • Oncology • Solid Tumor • CAFs • PAK1

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

Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma. (PubMed, EMBO Mol Med) - "Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL."

Journal • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Immunology • Infectious Disease • Inflammation • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • STAT3

PAK and PI3K pathway activation confers resistance to KRAS inhibitor sotorasib. (PubMed, Br J Cancer) - "Our results indicate that the cell-matrix interaction-dependent activation of PAK mediates resistance to sotorasib through the activation of MAPK and PI3K pathways."

Journal • Oncology • KRAS • PTEN

PAK1 and PAK2 in cell metabolism regulation. (PubMed, J Cell Biochem) - "The immediate effect of FRAX597, which inhibits PAK kinase activity, was moderate, indicating that PAK nonkinase functions are essential for cell metabolism...In contrast, PAK1 knockout resulted in increased glycolysis. However, the overall metabolic capacity was not substantially reduced by PAK1 or PAK2 deletion, possibly due to partial redundancy in PAK1/PAK2 regulatory roles or to activation of other compensatory mechanisms."

Journal • Hematological Malignancies • Leukemia • Lymphoma • Oncology • PAK2

CDK4/6 inhibition synergizes with inhibition of P21-Activated Kinases (PAKs) in lung cancer cell lines. (PubMed, PLoS One) - "To address this problem and to identify effective CDK4/6i combinations, we screened a library of targeted agents for efficacy in four non-small cell lung cancer lines treated with CDK4/6 inhibitors Palbociclib or Abemaciclib...Surprisingly, while the pan-PAK inhibitor PF03758309 synergizes with CDK4/6is, no synergy occurs with group I PAK inhibitors FRAX486 or FRAX597. Cell lines treated only with Ribociclib, FRAX486 or FRAX597 underwent G1/G0 arrest, whereas combination treatment with these compounds predominantly resulted in autophagy...Our results suggest that a unique combination of PAKs plays a crucial role in the synergy of PAK inhibitors with CDK4/6i. Targeting this unique PAK combination, could greatly improve the efficacy of CDK4/6i and broaden the spectrum of cancer treatment."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • RAC1

Water Mapping and Scoring approaches to predict the role of Hydration sites in Binding Affinity of PAK1 inhibitors. (PubMed, Comb Chem High Throughput Screen) - "This study determined the best scoring function, established SARs and predicted active molecules through a computational model. This will contribute towards development of the most potent PAK1 inhibitors."

Journal • CNS Disorders • Oncology

Group I p21-activated kinases in leukemia cell adhesion to fibronectin. (PubMed, Cell Adh Migr) - "FRAX597, which inhibits PAK kinase activity, increased cell-surface contact area in all leukemia cells. Both inhibitors reduced the stability of cell attachment and induced cell death."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FN1 • PAK2

p21-activated kinases as viable therapeutic targets for the treatment of high-risk Ewing sarcoma. (PubMed, Oncogene) - "Through expression knockdown and small-molecule inhibition of PAKs, utilizing FRAX-597, KPT-9274, and PF-3758309 in multiple ES cell lines and patient-derived xenograft models, we further explored the role of PAKs in ES tumor growth and metastatic capabilities. In addition, the analysis showed enrichment of anti-tumor immune regulatory mechanisms, including interferon (IFN)-ɣ and IFN-α responses. Altogether, our molecular and pre-clinical studies are the first to establish a critical role for PAKs in ES development and progression, and consequently as viable therapeutic targets for the treatment of high-risk ES in the near future."

Journal • Ewing Sarcoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

[VIRTUAL] The Expression of Paks and Its Clinical Significance in T-Cell Lymphoblastic Lymphoma (ASH 2020) - "Two PAK inhibitors, PF3758309 (PF) and FRAX597, were used to block PAK kinase activity pharmacologically...The synergistic effect between PAK inhibitor PF and doxorubicin was also observed (Figure 7)...Conclusions : PAK1 and PAK2 play certain roles in the occurrence and recurrence of T-LBL, and their potential as novel biomarkers deserves further exploring. Our results underscore the potential of PAK inhibitor as effective target therapy for T-LBL."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCND1 • NOTCH1 • PAK1

PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions. (PubMed, Sci Rep) - "Effects of PAK inhibition (IPA-3, FRAX597) or depletion (siRNA) on cell-surface adhesion were monitored by real-time microimpedance measurement...The impedance measurements indicate, that PAK2 depletion slows down cell attachment to a surface, and that PAK1-full is involved in cell spreading. Altogether, our data suggest a complex interplay among different PAK group I members, which have non-redundant functions."

Journal • Oncology