Potencies against functional endpoints in human B cells and peripheral blood mononuclear cells.

<p>Potencies against functional endpoints in human B cells and peripheral blood mononuclear cells.</p

BMS-986142 blocks neoantigen-induced antibody responses.

<p>(<b>A</b>) Primary anti-KLH antibody response over 14 days in mice: day 7 IgM (gray bars) and day 14 IgG (black bars) anti-KLH titers. Data shown are mean ± SEM. (<b>B</b>) Pharmacokinetics of BMS-986142 measured on day 14 of the study with the data represented as time after the morning dose. The dashed line represents the IC50 value determined <i>in vitro</i> against BCR-stimulated CD69 expression on B cells in mouse whole blood. ^*<i>p</i> < 0.05 versus vehicle group, <i>n</i> = 7–10/group.</p

BMS-986142 inhibits RANK-L-induced osteoclastogenesis in human monocytic precursors.

<p>(<b>A</b>) Quantitation of the number of TRAP-positive multinucleated cells per well after 9 days in culture. Data shown are mean ± standard deviation. ^*<i>p</i> < 0.05, ^**<i>p</i> < 0.01 versus vehicle group, n = 3/condition. (<b>B</b>) Representative images.</p

Inhibition of anti-IgM-stimulated phosphorylation of phospholipase C-γ2 in Ramos B cells by BMS-986142.

<p>Inhibition of anti-IgM-stimulated phosphorylation of phospholipase C-γ2 in Ramos B cells by BMS-986142.</p

BMS-986142 co-administered with CTLA-4-Ig shows an enhanced effect against CIA in mice.

<p>(<b>A</b>) Mean clinical scores over the course of the study, (<b>B</b>) mean clinical scores at the end of the study (day 37); BMS-986142 was administered by oral gavage once daily and CTLA-4-Ig by intraperitoneal injection twice weekly, and (<b>C</b>) total inflammation and bone resorption histology scores of the hind paws. Data shown as mean ± SEM. ^*<i>p</i> < 0.05 versus vehicle group, ^**<i>p</i> < 0.01 versus vehicle group, ^#<i>p</i> < 0.05 versus either treatment alone.</p

BMS-986142 is efficacious in the murine CAIA model.

<p>(<b>A</b>) Mean clinical scores, (<b>B</b>) histological evaluation of the right hind paws of CAIA mice, and (<b>C</b>) pharmacokinetics of BMS-986142 on day 12 of the CAIA study. Data shown are mean ± SEM. ^*<i>p</i> < 0.05 versus vehicle group, n = 7–10/group.</p

Therapeutic treatment with BMS-986142 co-administered with etanercept protected from CIA in mice.

<p>(<b>A</b>) Mean clinical scores over the course of the study, (<b>B</b>) mean clinical scores at the end of the study (day 41), (<b>C</b>) pharmacokinetics of BMS-986142 measured on the last day of the study with the data represented as time after the morning dose, (<b>D</b>) bone surface area measurements by micro-CT of the hind limbs, (<b>E</b>) bone mineral density measurements by micro-CT of the hind limbs, and (<b>F</b>) representative images of treatment groups using micro-CT. The dashed line represents the IC50 value determined <i>in vitro</i> against BCR-stimulated CD69 expression on B cells in mouse whole blood. Data for B, D, and E shown as mean ± SEM. ^*<i>p</i> < 0.05 versus vehicle group, ^#<i>p</i> < 0.05 versus either treatment alone, n = 9–10/group.</p

BMS-986142 is efficacious against CIA in mice.

<p>(<b>A</b>) Mean clinical scores over the course of the study, (<b>B</b>) mean clinical scores at the end of the study (day 46), (<b>C</b>) histological evaluation of the right hind paws, (D) plasma cells as measured by FACS analysis performed on spleens from 5 mice per group (3 mice in naïve group; non-immunized mice), (E) CD38 expression (MFI) on splenic CD138+B220low plasma cells, (F) anti-collagen II IgG titers, and (<b>G</b>) pharmacokinetics of BMS-986142 measured on the last day of the study with the data represented as time after the morning dose. The dashed line represents the IC50 value determined <i>in vitro</i> against BCR-stimulated CD69 expression on B cells in mouse whole blood. Data for <b>B</b> through <b>F</b> shown as mean ± SEM. ^*<i>p</i> < 0.05 versus vehicle group, ^#<i>p</i> < 0.05 versus either treatment alone, n = 10/group.</p

Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure–activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure–activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed