CE-224535 (PF-04905428)

Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer

The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on immune cells and is highly upregulated in a number of human cancers where it can play a trophic role in tumorigenesis. Activation of this receptor leads to the formation of a non-selective cation channel, which has been associated with several cellular functions mediated by the PI3K/Akt pathway and protein kinases. Due to its broad range of functions, the receptor represents a potential therapeutic target for a number of cancers. This review describes the range of mechanisms associated with P2X7R activation in cancer settings and highlights the potential of targeted inhibition of P2X7R as a therapy. It also describes in detail a number of key P2X7R antagonists currently in pre-clinical and clinical development, including oxidised ATP, Brilliant Blue G (BBG), KN-62, KN-04, A740003, A438079, GSK1482160, CE-224535, JNJ-54175446, JNJ-55308942, and AZ10606120. Lastly, it summarises the in vivo studies and clinical trials associated with the use and development of these P2X7R antagonists in different disease contexts.

P2X receptors: Insights from the study of the domestic dog

Fifty years ago, the late Geoffrey Burnstock described the concept of purinergic nerves and transmission bringing into existence the broader concepts of purinergic signaling including P2X receptors. These receptors are trimeric ligand-gated cation channels activated by extracellular adenosine 5'-triphosphate (ATP). P2X receptors have important roles in health and disease and continue to gain interest as potential therapeutic targets in inflammatory, neurological, cardiovascular and many other disorders including cancer. Current understanding of P2X receptors has largely arisen from the study of these receptors in humans and rodents, but additional insights have been obtained from the study of P2X receptors in the domestic dog, Canis familiaris. This review article will briefly introduce purinergic signaling and P2X receptors, before detailing the pharmacological profiles of the two recombinant canine P2X receptors studied to date, P2X7 and P2X4. The article will then describe the current state of knowledge concerning the distribution and function of the P2X receptor family in dogs. The article will also discuss the characterization of single nucleotide polymorphisms in the canine P2RX7 gene, and contrast this variation to the canine P2RX4 gene, which is largely conserved between dogs. Finally, this article will outline published examples of the use of dogs to study the pharmacokinetics of P2X7 and P2X3 antagonists, and how they have contributed to the preclinical testing of antagonists to human P2X7, CE-224,535, and human P2X3, Gefapixant (AF-219, MK-7264) and Eliapixant (BAY, 1817080), with Gefapixant gaining recent approval for use in the treatment of refractory chronic cough in humans. This article is part of the Special Issue on 'Purinergic Signaling: 50 years'.

Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate

Objective: To evaluate efficacy and safety of CE-224,535, a selective P2X(7) receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX).
Methods: In our phase IIA study (ClinicalTrials.gov no. NCT00628095; A6341009), patients aged ≥ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of ≥ 7.5 mg MTX.
Results: The American College of Rheumatology 20% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0% vs 36.2%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3% (CE-224,535) and 55.3% (placebo) of patients; the most common AE were nausea (11.3%, CE-224,535; 4.3%, placebo) and diarrhea (7.5%, CE-224,535; 4.3%, placebo). The proportion of patients discontinuing due to an AE was 9.4% (CE-224,535) and 6.4% (placebo); no deaths were reported. Serious AE occurred in 3.8% (CE-224,535) and 2.1% (placebo) of patients; none was considered treatment-related.
Conclusion: CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.

Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535

High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.