IC50 Values of PRT3789 for Anti-Proliferation in Various Tumor Cell Lines in 2D In Vitro Assay

PRT3789 enhances the efficacy of KRAS G12C inhibitors in SMARCA4-deficient cancer models

PRT3789 single dose decreases SMARCA2 protein and KRT80 mRNA expression in NCI-H838 CDX model in mice

PRT3789 and chemotherapy combination were well tolerated in mice with no drug-drug interaction

Pre-Clinical In Vivo Model Summary

PRT3789 induced SMARCA2/4 ternary complexes and selective ubiquitination

VHL-based ternary complex in Protein Data Bank

SMARCA2 bromodomain structures in Protein Data Bank

IC50 Values of PRT3789 compared to Example 38 for Anti-Proliferation in SMARCA4 WT Tumor Cell Lines in 2D In Vitro Assay

Mechanistic and synergy profiling of PRT3789 in combination with docetaxel

PRT3789 regulates cell cycle in SMARCA4-deficient cancer cells

PRT3789 shows species-specific selectivity and induces SMARCA2 degradation through the ubiquitin–proteasome system

PRT3789 effects on cell lines with SMARCA4 class II missense mutations

Antibodies and markers used for spectral flowcytometry.

The adoptive transfer model mimics pathways that are constitutively activated in human MCL.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but aggressive and potentially lethal hyperinflammatory syndrome characterized by pathologic immune activation and excessive production of proinflammatory cytokines leading to tissue damage and multisystem organ failure. There is an urgent need for the discovery of novel targets and development of therapeutic strategies to treat this rare but deadly syndrome. Protein Arginine Methyltransferase 5 (PRMT5) mediates T cell-based inflammatory responses, making it a potential actionable target for the treatment of HLH. Using CPG-1826 and anti-IL10R antibody, we induced murine secondary HLH in vivo with a marked expansion of splenic myeloid cell subsets and concurrent reduction of T and NK cell populations. PRMT5 expression was significantly upregulated in splenic T and NK lymphocytes as well as monocytes and dendritic cells in mice with HLH (p<0.05). Treatment with PRT382, a potent and selective PRMT5 inhibitor, significantly reduced physical signs of secondary HLH, including splenomegaly, hepatomegaly and anemia (p<0.0001 in each case), when compared to untreated mice. Inflammatory cytokines known to drive hyperinflammation in HLH, including IFNγ and IL-6 were reduced to healthy levels with PRT382 treatment (p>0.999 for both). PRT382 treatment also reduced the expansion of myeloid cell populations (p<0.0001) in mice with HLH, compared to untreated mice, while restoring T and NK cell numbers (p<0.001 for both). These results identify PRMT5 as a promising target for the management of secondary HLH and justify further exploration in this and other models of hyperinflammation.

Reagents used for histology and immunohistochemistry

Disease characteristics of the mice that developed lymphoma

Disease characteristics of the mice that developed lymphoma

Disease characteristics of the mice that developed lymphoma