Delving into the Latest Updates on Seletalisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

UCB-5857

Target

PI3Kδ

Action-

Mechanism

PI3Kδ inhibitors(Phosphatidylinositol 3 kinase delta inhibitors)

Therapeutic Areas

Immune System DiseasesCongenital DisordersOther Diseases+ [4]

Active Indication-

Inactive Indication

Activated PI3K-delta SyndromeArthritis, PsoriaticPlaque psoriasis+ [2]

Originator Organization

UCB SA

Active Organization-

Inactive Organization

UCB Celltech

UCB SA

UCB Pharma GmbH

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

RegulationOrphan Drug (United States), Orphan Drug (European Union)

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Structure/Sequence

Molecular FormulaC23H14ClF3N6O

InChIKeyLNLJHGXOFYUARS-OAQYLSRUSA-N

CAS Registry1362850-20-1

This is a Phase 2, multicenter, double-blind, placebo-controlled, 12-week proof-of-concept study to assess the efficacy, safety, and tolerability of UCB5857 in subjects with primary Sjögren's Syndrome (pSS).
The primary objective of this study is to evaluate the efficacy on overall disease activity and safety of UCB5857 added to current treatment relative to placebo in subjects with pSS.

Start Date01 Oct 2015

Sponsor / Collaborator

UCB Celltech

[+1]

100 Clinical Results associated with Seletalisib

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100 Translational Medicine associated with Seletalisib

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100 Patents (Medical) associated with Seletalisib

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16

Literatures (Medical) associated with Seletalisib

24 Aug 2022·Journal of leukocyte biologyQ3 · MEDICINE

The phosphoinositide-3-kinase (PI3K)-delta inhibitor seletalisib impairs monocyte-derived dendritic cells maturation, APC function, and promotes their migration to CCR7 and CXCR4 ligands

Q3 · MEDICINE

Article

Author: Cavani, Andrea ; Madonna, Stefania ; Dimartino, Valentina ; Cattani, Caterina ; Mirisola, Concetta ; Costanzo, Gianfranco ; Scopelliti, Fernanda ; Albanesi, Cristina ; Mercurio, Laura

Abstract:

PI3K pathway plays a crucial role in dendritic cells (DCs) functions, as it regulates different cellular processes, such as maturation and cytokines production. However, the specific role of PI3K p110δ isoform in human DCs has not been thoroughly addressed. In this study, we analyze the effects of seletalisib, a potent and specific inhibitor of PI3K p110δ, on phenotype and antigen-presenting functions of monocyte-derived DCs undergone maturation via LPS. Seletalisib treatment reduced membrane HLA-DR as well as CD83 and CD40 costimulatory molecules, whereas CD80 and CD86 expression was only partially affected. Additionally, DCs cultures showed reduced TNF-α, IL-10, and IL-12 and increased IL-23 secretion levels. This resulted in a reduced capacity of DCs to prime allogeneic T cells, with a strong decrease of Th1 differentiation. On the other hand, PI3K p110δ inhibitor seletalisib increased CXCR4 and CCR7 expression and augmented the DCs migration toward CCL19 and CXCL12 ligands. At molecular level, inhibition of PI3K p110δ isoform by seletalisib significantly down-regulated the phosphorylation of AKT and other downstream signaling molecules, such as ribosomal protein S6, 4E-BP1, and NF-κB p65. In contrast, seletalisib did not affect p38 MAP kinase phosphorylation or TLR-associated adapter molecule TIRAP in DCs. Our results indicate that PI3K p110δ can serve as an important regulatory signal for DCs, and selective inhibition of PI3K p110δ isoform by seletalisib could be used for the prevention of exaggerated and harmful immune responses occurring in pathologic conditions, such as autoimmune disorders.

08 Jul 2021·Journal of medicinal chemistryQ1 · MEDICINE

Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases

Q1 · MEDICINE

Article

Author: Yang, Zhuang ; Zhang, Chufeng ; Liu, Kongjun ; Shi, Mingsong ; Deng, Dexin ; Liu, Jiang ; Chen, Lijuan ; Yuan, Xue ; Li, Dan ; Yang, Tao ; Zhao, Min ; Tang, Minghai ; Zheng, Wei ; Chen, Yong

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.

02 Mar 2021·Rheumatology (Oxford, England)Q2 · MEDICINE

A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome

Q2 · MEDICINE

Article

Author: Giacomelli, Roberto ; Mariette, Xavier ; Nayar, Saba ; Johnston, Geoffrey I ; Barone, Francesca ; Payne, Andrew ; Cain, Dionne ; Williams, Paulette ; Triolo, Giovanni ; Juarez, Maria ; Devauchelle-Pensec, Valerie ; Ng, Wan Fai ; Sánchez Bursón, Juan ; Bowman, Simon J ; Diaz, Nieves ; Helmer, Eric ; Fisher, Benjamin A ; Guggino, Giuliana ; Gottenberg, Jacques-Eric ; Kvarnström, Marika ; Rosas, José

Abstract:

Objectives:

This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren’s syndrome (PSS).

Methods:

Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies.

Results:

Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: –2.59 (95% CI: –7.30, 2.11; P=0.266) and –1.55 (95% CI: –3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo.

Conclusion:

Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation.

Trial registration:

https://clinicaltrials.gov, NCT02610543.

100 Deals associated with Seletalisib

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12706

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Activated PI3K-delta Syndrome	Phase 3	France	UCB SA	08 Jun 2016
Primary Sjögren's syndrome	Phase 2	France	UCB Celltech	01 Oct 2015
Primary Sjögren's syndrome	Phase 2	Italy	UCB Celltech	01 Oct 2015
Primary Sjögren's syndrome	Phase 2	Spain	UCB Celltech	01 Oct 2015
Primary Sjögren's syndrome	Phase 2	Sweden	UCB Celltech	01 Oct 2015
Primary Sjögren's syndrome	Phase 2	United Kingdom	UCB Celltech	01 Oct 2015
Sjogren's Syndrome	Phase 2	Greece	UCB SA	-
Arthritis, Psoriatic	Phase 1	United Kingdom	UCB Pharma GmbH	01 Aug 2013
Plaque psoriasis	Phase 1	United Kingdom	UCB SA	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02610543 (Pubmed \| Rheumatology (Oxford)) Manual	Phase 2	Primary Sjögren's syndrome	27	seletalisib	ahhjgkqazx(tsvavitomv): Difference = -2.59 (95% CI, 2.11 - 7.30), P-Value = 0.266 View more	Positive	02 Mar 2021
				Placebo
NCT02610543 (Phase II, EULAR2019)	Phase 2	Primary Sjögren's syndrome EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI)	27	Seletalisib	caayfeshso(zjpvxhdkrn) = mbkseydqbb ggmnchqtwg (vtyaueoxrx, 1.7) View more	Positive	12 Jun 2019
				Placebo	caayfeshso(zjpvxhdkrn) = tlndvtjgtu ggmnchqtwg (vtyaueoxrx, 1.5) View more
NCT02207595 \| NCT02303509 (Pubmed \| Eur J Clin Pharmacol) Manual	Phase 1	Inflammation \| Immune System Diseases	-	seletalisib (90 mg QD)	ptnpmckvtt(zqfxdkjulq) = yjcrfsykcz jgvcearhzf (nekzrhyazb )	Positive	01 May 2017
				seletalisib (30 mg BID)	ptnpmckvtt(zqfxdkjulq) = zvxsrepaxt jgvcearhzf (nekzrhyazb )