PF-00477736 / Pfizer - LARVOL DELTA

Manganese-coordinated nanoparticles loaded with CHK1 inhibitor dually activate cGAS-STING pathway and enhance efficacy of immune checkpoint therapy. (PubMed, Biomaterials) - "In this study, we designed and fabricated manganese-containing nanoparticles loaded with the CHK1 inhibitor PF477736, which were subsequently encapsulated with macrophage membrane (PF/MMSN@MPM)...Moreover, the combination of PF/MMSN@MPM with anti-PD-1 (αPD-1) exhibited a stronger therapeutic effect compared to αPD-1 alone. PF/MMSN@MPM precisely and synergistically activated the cGAS-STING pathway, significantly improving therapeutic efficacy of ICB, and offering promising potential for tumor therapy."

Journal • Oncology • CGAS • STING

PF-477736 modulates vascular smooth muscle cells phenotypic transition through Chk1/p53/CD44 pathway. (PubMed, Tissue Cell) - "Our findings show that PF-477736 exerts anti-vascular remodeling effect by inhibiting phenotypic transition through the Chk1/p53/CD44 pathway in VSMCs, providing novel therapeutic strategies for preventing and treating vascular remodeling."

Journal • Oncology • CD44 • CHEK1 • PCNA • VIM

Combined inhibition of RAD51 and CHK1 causes synergistic toxicity in cisplatin resistant cancer cells by triggering replication fork collapse. (PubMed, Int J Cancer) - "Synergistic cytolethal effects were achieved after combined treatment with low to moderate doses of the non-genotoxic RAD51-inhibitor (RAD51i) B02 and CHK1-inhibitor (CHK1i) PF477736. Based on these data, we suggest combined inhibition of RAD51 and CHK1 to overcome acquired cisplatin resistance of malignant cells. We propose that the molecular mechanism of this synergistic toxicity relies on a simultaneous inactivation of two key DNA damage tolerance pathways regulating replication fork restart, thereby circumventing the activation of alternative compensatory mechanisms and, in consequence, eventually effectively triggering apoptotic cell death by replication fork collapse."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CHEK1 • RAD51

ATR, CHK1 and WEE1 inhibitors cause homologous recombination repair deficiency to induce synthetic lethality with PARP inhibitors. (PubMed, Br J Cancer) - "Our data indicate that, rather than acting via abrogation of cell cycle checkpoints, ATR, CHK1 and WEE1 inhibitors cause an HRD phenotype and hence "induced synthetic lethality" with PARPi."

Journal • Synthetic lethality • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • HRD • RAD51

αGal9Ab Treatment As a Novel Therapy for Blood Cancer (ASH 2023) - "Notably, αGAL-9Ab treatment synergized with multiple CHEK1 inhibitorscurrently being tested in phase I or II clinical trials (GDC-0575, Prexasertib and PF477736) to enhance the in vitro killing of human T-ALL, B-ALL, and AML cells. In conclusion, single-agent αGAL-9Ab treatment appears to be cytotoxic against multiple acute leukemia subtypes ( ALs) and its efficacy is enhanced with CHEK1 inhibition. To validate this novel combinatorial approach for treating ALs, additional studies need to be performed to define the mechanisms of action and further pre-clinical experiments will be invaluable in determining the efficacy and safety of these therapies."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • CHEK1 • LGALS9 • MCL1

Identification of inhibitors for the trans-membrane Trypanosoma cruzi eIF2α kinase relevant for parasite proliferation. (PubMed, J Biol Chem) - "Only Dasatinib and PF-477736, inhibitors of Src/Abl and ChK1 kinases, showed inhibitory activity with IC50 of 0.2 ± 0.02 mM and 0.8 ± 0.1, respectively. In infected cells Dasatinib inhibited growth of parental amastigotes (IC50 = 0.6 ± 0.2 mM) but not TcK2 of depleted parasites (IC50 > 34 mM) identifying Dasatinib as a potential lead for development of therapeutics for Chagas disease targeting TcK2."

Journal • CHEK1

Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy. (PubMed, Cancers (Basel)) - "We have directly compared, for the first time, the cytotoxicity of four DDR inhibitors (rucaparib/PARPi, VE-821/ATRi, PF-477736/CHK1i and MK-1775/WEE1i) as single agents, and in combination with cisplatin and radiotherapy (RT) in a panel of CC cells. In mice, cisplatin-induced acute kidney injury was associated with oxidative stress and PARP activation and was prevented by rucaparib. Therefore, while all inhibitors investigated may increase the efficacy of CRT, the greatest clinical potential of rucaparib may be in limiting kidney damage, which is dose-limiting."

Journal • Acute Kidney Injury • Cervical Cancer • Nephrology • Oncology • Renal Disease • Solid Tumor • CHEK1

Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations study for the identification of LIM kinase-1 inhibitors. (PubMed, J Biomol Struct Dyn) - "The pharmacophoric features of PF-00477736 were used to screen the Zinc15 compounds library...The docking score was found to be -8.85, -7.50 and -7.68 kcal/mol. These hits exhibited optimal binding properties with the target in docking study, blood-brain barrier permeability, in silico pharmacokinetics and low predicted toxicity.Communicated by Ramaswamy H. Sarma."

Journal • Alzheimer's Disease • CNS Disorders • Pain