PRT062607 / Biogen, AstraZeneca - LARVOL DELTA

A Phase 1 Study to Evaluate the Safety and Tolerability of Escalating Doses of Fostamatinib in Subjects with Stable Sickle Cell Disease: Trial in Progress (ASH 2024) - P1 | "We compared the effects of different SYK inhibitors (Imatinib, R112, PRT062607, Endospletinib, Fostamatinib, R406, and cerdulatinib) on the fraction of sickled RBCs vs time following deoxygenation of HbSS RBCs, and showed that R406 slowed the kinetics of sickling while the effect of imatinib on sickling kinetics was minimal...Not eligible : history of neutropenia (unrelated to drug suppression), history of poorly controlled blood pressure, currently receiving treatment with SCD therapies (excluding hydroxyurea) or history of gene therapy, bone marrow or stem cell transplantation...Conclusion : This study will evaluate the safety and tolerability of fostamatinib across the tested dose levels in adults with SCD. The accompanying changes in the active metabolite of fostamatinib, R406, with changes in tyrosine phosphorylation of RBC membrane band 3, sickling kinetics, deformability, and in micro-vesicle release will determine whether fostamatinib treatment could be..."

Clinical • P1 data • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Immune Thrombocytopenic Purpura • Infectious Disease • Neutropenia • Novel Coronavirus Disease • Sickle Cell Disease • Thrombocytopenia • Thrombocytopenic Purpura • SYK

The role of SYK phosphorylation in LPS-induced immunoglobulin responses of B cells in large yellow croaker (Larimichthys crocea). (PubMed, Fish Shellfish Immunol) - "Moreover, when we used PRT062607 HCl to inhibit the phosphorylation of LcSYK, both mRNA expression and protein production of IgM in IgM+ B cells were significantly suppressed. These results suggest that SYK phosphorylation may play a role in LPS-induced IgM production by IgM+ B cells, improving our understanding of the role of SYK in immunoglobulin responses of B cells in fish."

Journal • SYK

Spleen tyrosine kinase: a novel pharmacological target for sepsis-induced cardiac dysfunction and multi-organ failure. (PubMed, Front Immunol) - "Thus, we investigated the effects of the highly selective SYK inhibitor PRT062607 (15mg/kg; i.p.) on sepsis-induced cardiac dysfunction and MOF in a clinically-relevant, murine model of sepsis...Antibiotics (imipenem/cilastatin; 2mg/kg; s.c.) and analgesic (buprenorphine; 0.05mg/kg; i.p.) were administered at 6h and 18h post-CLP...These results demonstrate, for the first time, that SYK inhibition 1h after the onset of sepsis reduces the systemic inflammation, cardiac dysfunction and MOF, suggesting a potential role of the activation of SYK in the pathophysiology of sepsis. Novel therapeutic strategies that inhibit SYK activity may be of benefit in patients with diseases associated with local or systemic inflammation including sepsis."

Journal • Hepatology • Infectious Disease • Inflammation • Liver Failure • Nephrology • Pain • Renal Disease • Septic Shock • NLRP3 • SYK

Identification and structural characterization of small molecule inhibitors of PINK1. (PubMed, Sci Rep) - "The crystal structures of insect PINK1 bound to PRT062607 or CYC116 reveal how the compounds interact with the ATP-binding pocket. PRT062607 notably engages with the catalytic aspartate and causes a destabilization of insert-2 at the autophosphorylation dimer interface. While PRT062607 is not selective for PINK1, it provides a scaffold for the development of more selective and potent inhibitors of PINK1 that could be used as chemical probes."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Targeted Protein Degradation • SYK

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain. (PubMed, Br J Pharmacol) - "Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties."

Journal • Immunology • Neuralgia • Pain • SYK

Syk inhibitors protect against microglia-mediated neuronal loss in culture. (PubMed, Front Aging Neurosci) - "We found that the Syk inhibitors BAY61-3606 and P505-15 (at 1 and 10 μM, respectively) completely prevented the neuronal loss induced by LPS, which was microglia-dependent...Thus, Syk inhibition in this model is most likely neuroprotective by reducing microglial phagocytosis, however, the reduced microglial density and IL-6 release may also contribute. This work adds to increasing evidence that Syk is a key regulator of the microglial contribution to neurodegenerative disease and suggests that Syk inhibitors may be used to prevent excessive microglial phagocytosis of synapses and neurons."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • IL6 • SYK • TNFA

Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases. (PubMed, Expert Opin Investig Drugs) - "The search terms used were SYK inhibitors, R406, fostamatinib (R788), P505-15 (PRT062607), entospletinib (GS-9973), R112, lanraplenib (GS-9876), cerdulatinib, R343, BAY-61-3606, GSK compound 143 (GSK143), R211, SKI-G-618, SKI-O-85, ER-27319, YM193306, RO9021 in conjunction with autoimmune disease using electronic databases including PubMed, EMBASE, MEDLINE and Google Scholar. However, the difficulties in developing highly selective SYK inhibitors and the unknown effects are challenges. Long term and real-world data are essential to determine the risk-benefit ratio and true role of SYK inhibitors in the therapy of ADs."

Journal • Immunology • Inflammation • SYK

Spleen Tyrosine Kinase (SYK) Inhibitor PRT062607 Protects Against Ovariectomy-Induced Bone Loss and Breast Cancer-Induced Bone Destruction. (PubMed, Biochem Pharmacol) - "Further, we proved that PRT could prevent post-ovariectomy (OVX) loss of bone and breast cancer-induced bone destruction in vivo, which agreed with the in vitro outcomes. In conclusion, our findings suggest the potential value of PRT in managing osteolytic diseases mediated by osteoclasts."

Journal • Breast Cancer • Oncology • Osteoporosis • Rheumatology • Solid Tumor • SYK

The Role of Syk in Inflammatory Response of Human Abdominal Aortic Aneurysm Tissue. (PubMed, Ann Vasc Dis) - "Secretions of IL-6 and MMP-9 were enhanced by exogenous normal human immunoglobulin G (IgG), which was suppressed by P505-15, whereas secretion of MMP-2 was insensitive to IgG or P505-15. These results demonstrate an important role of Syk for IgG-dependent inflammatory response in human AAA."

Journal • Cardiovascular • Immunology • IL6 • MMP2 • MMP9 • SYK

Systematic Investigation of Microenvironmental Drug Resistance Mechanisms in Chronic Lymphocytic Leukemia (ASH 2019) - "We found drug response profiles to be correlated closely for drugs targeting the same signaling-pathway, e.g. the B-cell receptor inhibitors Ibrutinib (BTK) and PRT062607 (Syk) (Pearson correlation coefficient: r=0.78, 95% CI: 0.72 - 0.83)...3) The microenvironmental stimulus and the drug exhibited no major individual effect on CLL cell survival, but together significantly increased CLL cell viability (e.g. Interferon-γ:Ralimetinib, p-value: < 0.0001)...A high signaling activity of IL-4 was associated with shorter time to treatment, indicating that CLL progresses faster with strong microenvironmental support. Conclusion We present a systematic investigation on the tumor microenvironment in CLL, the underlying molecular determinants as well its interference with drug response which will serve as a scientific resource and starting point for further mechanistical investigations."

IO Biomarker • CD40LG • IL2 • IL4 • IL6 • SYK

Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis. (PubMed, Oncogene) - "We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis...Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFα CD206 phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis."

Journal

Targeting Syk Signaling in Myeloid Cells Protects against Liver Fibrosis and Hepatocarcinogenesis (ATC 2019) - "...In select experiments, mice were treated with thrice weekly with Piceatannol (20mg/kg; Selleckchem; Houston, TX), PRT062607 (15mg/kg; Selleckchem; Houston, TX), or corn oil via oral gavage for 12 weeks... Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis."

Late-breaking abstract