Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

Cushing, Timothy D.; Hao, Xiaolin; Shin, Youngsook; Andrews, Kristin L.; Brown, Matthew F.; Cardozo, Mario; Chen, Yi; Duquette, Jason; Fisher, Ben; Turiso, Felix González-López de; He, Xiao; Henne, Kirk R.; Hu, Yiling; Hungate, Randall W.; Johnson, Michael G.; Kelly, Ron C.; Lucas, Brian S.; McCarter, John D.; McGee, Lawrence R.; Medina, Julio C.; Miguel, Tisha San; Mohn, Deanna; Pattaropong, Vatee; Pettus, Liping H.; Reichelt, Andreas; Rzasa, Robert M.; Seganish, Jennifer L.; Tasker, Andrew S.; Wahl, R.; Wannberg, Sharon; Whittington, Douglas A.; Whoriskey, John; Yu, Gang; Zalameda, Leeanne; Zhang, Dawei; Metz, Daniela

doi:10.1021/jm501624r

Cited by 78 publications

(47 citation statements)

References 42 publications

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“…For example, IC87114 reduced autoantibody production in a rat model of collagen-induced arthritis (9). Another recently developed p110δ inhibitor, AMG319, reduced KLH-specific IgM and IgG production in vivo (10) while duvelisib (IPI-145), a dual p110δ/γ inhibitor, showed potent activity in reducing inflammation in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models (11). Currently, however, there are no approved treatments targeting p110δ in B-cell-mediated autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

The Selective Phosphoinoside-3-Kinase p110δ Inhibitor IPI-3063 Potently Suppresses B Cell Survival, Proliferation, and Differentiation

et al. 2017

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The class I phosphoinoside-3-kinases (PI3Ks) are important enzymes that relay signals from cell surface receptors to downstream mediators driving cellular functions. Elevated PI3K signaling is found in B cell malignancies and lymphocytes of patients with autoimmune disease. The p110δ catalytic isoform of PI3K is a rational target since it is critical for B lymphocyte development, survival, activation, and differentiation. In addition, activating mutations in PIK3CD encoding p110δ cause a human immunodeficiency known as activated PI3K delta syndrome. Currently, idelalisib is the only selective p110δ inhibitor that has been FDA approved to treat certain B cell malignancies. p110δ inhibitors can suppress autoantibody production in mouse models, but limited clinical trials in human autoimmunity have been performed with PI3K inhibitors to date. Thus, there is a need for additional tools to understand the effect of pharmacological inhibition of PI3K isoforms in lymphocytes. In this study, we tested the effects of a potent and selective p110δ inhibitor, IPI-3063, in assays of B cell function. We found that IPI-3063 potently reduced mouse B cell proliferation, survival, and plasmablast differentiation while increasing antibody class switching to IgG1, almost to the same degree as a pan-PI3K inhibitor. Similarly, IPI-3063 potently inhibited human B cell proliferation in vitro. The p110γ isoform has partially overlapping roles with p110δ in B cell development, but little is known about its role in B cell function. We found that the p110γ inhibitor AS-252424 had no significant impact on B cell responses. A novel dual p110δ/γ inhibitor, IPI-443, had comparable effects to p110δ inhibition alone. These findings show that p110δ is the dominant isoform mediating B cell responses and establish that IPI-3063 is a highly potent molecule useful for studying p110δ function in immune cells.

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Section: Introductionmentioning

confidence: 99%

The Selective Phosphoinoside-3-Kinase p110δ Inhibitor IPI-3063 Potently Suppresses B Cell Survival, Proliferation, and Differentiation

et al. 2017

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“…The PI3Kδ isoform is the most important isoform in hematologic cells and has been implicated as a potential target for the treatment of hematological malignancies . Recently, several new PI3Kδ isoform‐selective inhibitors showing improved selectivity and potency have been reported . In the current study, puquitinib was characterized as a novel PI3Kδ inhibitor, and was shown to significantly and selectively inhibit PI3Kδ activity, notably outperforming CAL‐101 both in vitro and in vivo against AML.…”

Section: Discussionmentioning

confidence: 85%

“…(28) Recently, several new PI3Kd isoform-selective inhibitors showing improved selectivity and potency have been reported. (12,13) In the current study, puquitinib was characterized as a novel PI3Kd inhibitor, and was shown to significantly and selectively inhibit PI3Kd activity, notably outperforming CAL-101 both in vitro and in vivo against AML. This promising pharmaceutical activity may support the potential clinical use of puquitinib for the treatment of AML.…”

Section: Discussionmentioning

confidence: 90%

“…(11) Currently, there are several PI3Kd inhibitors at different stages of clinical development, including AMG319, GSK226955 and INCB040093. (12,13) Idelalisib (GS-1101, CAL-101), a more potent derivative of the highly p110d-selective inhibitor, IC87114, was approved recently to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma, another type of non-Hodgkin lymphoma. (14) Acute myeloid leukemia is the most common acute leukemia in adults and is among the most lethal.…”

mentioning

confidence: 99%

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Puquitinib, a novel orally available PI3Kδ inhibitor, exhibits potent antitumor efficacy against acute myeloid leukemia

Xie

Zhen

et al. 2017

Cancer Science

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The PI3Kδ isoform (PIK3CD), also known as P110δ, is predominately expressed in leukocytes and has been implicated as a potential target in the treatment of hematological malignancies. In this report, we detailed the pharmacologic properties of puquitinib, a novel, orally available PI3Kδ inhibitor. Puquitinib, which binds to the ATP‐binding pocket of PI3Kδ, was highly selective and potent for PI3Kδ relative to other PI3K isoforms and a panel of protein kinases, exhibiting low‐nanomolar biochemical and cellular inhibitory potencies. Additional cellular profiling demonstrated that puquitinib inhibited proliferation, induced G1‐phase cell‐cycle arrest and apoptosis in acute myeloid leukemia (AML) cell lines, through downregulation of PI3K signaling. In in vivo AML xenografts, puquitinib alone showed stronger efficacy than the well‐known p110δ inhibitor, CAL‐101, in association with a reduction in AKT and ERK phosphorylation in tumor tissues, without causing noticeable toxicity. Furthermore, the combination of puquitinib with cytotoxic drugs, especially daunorubicin, yielded significantly stronger antitumor efficacy compared with each agent alone. Thus, puquitinib is a promising agent with pharmacologic properties that are favorable for the treatment of AML.

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“…ACP-319 (known as AMG-319 before acquisition by Acerta) inhibits p110δ with submicromolar affinity in cell-free assays (Table 1) [46]. The phase 1 first-in-human study was completed in subjects with CLL and iNHL with results reported in abstract form [97].…”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Lampson

Brown

2017

Expert Opinion on Investigational Drugs

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Introduction Phosphatidylinositol-3-kinase (PI3K) inhibitors comprise a novel class of agents that are effective for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL). The demonstrated efficacy and subsequent FDA approval of the prototypical PI3Kδ inhibitor idelalisib has led to development of multiple compounds targeting this pathway. Areas Covered We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of tonic signaling from the B cell receptor, blockade of pro-survival signals from the microenvironment, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections and sepsis (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We then summarize PI3K inhibitors that have entered clinical trials for the treatment of lymphoma, focusing on agents with significant selectivity for PI3Kα and PI3Kδ. Expert Opinion PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, in comparison to other novel agents, idelalisib has infectious and autoimmune toxicities that have limited its use. Outside of clinical trials, the use of PI3K inhibitors should be restricted to CLL patients who have progressed on ibrutinib or iNHL patients who have progressed on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

show abstract

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

Cited by 78 publications

References 42 publications

The Selective Phosphoinoside-3-Kinase p110δ Inhibitor IPI-3063 Potently Suppresses B Cell Survival, Proliferation, and Differentiation

The Selective Phosphoinoside-3-Kinase p110δ Inhibitor IPI-3063 Potently Suppresses B Cell Survival, Proliferation, and Differentiation

Puquitinib, a novel orally available PI3Kδ inhibitor, exhibits potent antitumor efficacy against acute myeloid leukemia

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

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