Delving into the Latest Updates on Motolimod with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Motolimod (USAN/INN)

Target

TLR8

Mechanism

TLR8 agonists(Toll like receptor 8 agonists)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication

Head and Neck NeoplasmsOvarian CancerPeritoneal Neoplasms

Inactive Indication

Advanced cancerAdvanced Malignant Solid NeoplasmB-Cell Lymphoma+ [7]

Originator Organization

Array BioPharma, Inc.

Active Organization

Array BioPharma, Inc.

Inactive Organization

Celgene Corp.

MedImmune LLC

Presage Biosciences, Inc.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC28H34N4O2

InChIKeyQSPOQCXMGPDIHI-UHFFFAOYSA-N

CAS Registry926927-61-9

This is a multi-center, single arm, open-label, multi-agent, localized pharmacodynamic biomarker Phase 0 trial designed to study the biological effects within the tumor microenvironment of motolimod and motolimod combined with nivolumab when administered intratumorally in microdose quantities via the CIVO device in patients with head and neck squamous cell carcinoma (HNSCC). CIVO stands for comparative in vivo oncology.

Start Date15 Oct 2021

Sponsor / Collaborator

Presage Biosciences, Inc.

[+2]

NCT03906526 / TerminatedPhase 1

A Phase 1b Multicenter Pre-Surgical Study to Evaluate Immune Biomarker Modulation in Response to Motolimod (VTX-2337) in Combination With Nivolumab in Subjects With Resectable Squamous Cell Carcinoma of the Head and Neck (SCCHN)

This is an open label, Phase 1b pre-operative window of opportunity biomarker trial to analyze the combination of intravenous (IV) anti-PD-1 inhibitor, nivolumab, given along with toll-like receptor 8 (TLR 8) agonist motolimod delivered either subcutaneously (SC) or by intratumoral injection (IT) in subjects with squamous cell carcinoma of the head and neck (SCCHN). Subjects with previously untreated, resectable SCCHN, will be recruited onto this trial and will initially undergo pre-treatment diagnostic imaging and biological sample collection. These subjects will undergo pre-operative study treatment for a 3 to 4-week period prior to a scheduled surgical resection.

Start Date03 Jul 2019

Sponsor / Collaborator

Celgene Corp.

NCT02431559 / CompletedPhase 1/2IIT

Phase 1/2 Study of Chemoimmunotherapy With Toll-like Receptor 8 Agonist Motolimod (VTX-2337) + Anti-PD-L1 Antibody MEDI4736 in Subjects With Recurrent, Platinum-Resistant Ovarian Cancer for Whom Pegylated Liposomal Doxorubicin is Indicated

This is an ongoing Phase 1/2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with recurrent, platinum-resistant ovarian cancer who are scheduled to receive pegylated liposomal doxorubicin (PLD).The primary objective of Phase 1 is to determine the maximum tolerated dose (MTD) and safety profile, with a secondary objective to evaluate the clinical efficacy as measured by progression-free survival (PFS) rate at 6 months (PFS-6). The primary objective of Phase 2 is the evaluation of clinical efficacy as measured by PFS-6. For both phases, secondary objectives include evaluation of clinical efficacy as measured by overall response rate, PFS, and overall survival (OS), safety and tolerability, and immunological responses.

Start Date02 Dec 2015

Sponsor / Collaborator

Ludwig Institute for Cancer Research Ltd.

[+3]

100 Clinical Results associated with Motolimod

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100 Translational Medicine associated with Motolimod

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100 Patents (Medical) associated with Motolimod

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26

Literatures (Medical) associated with Motolimod

03 May 2024·Rheumatology

TLR8 aggravates skin inflammation and fibrosis by activating skin fibroblasts in systemic sclerosis

Article

Author: Gao, Jian ; Tang, Yulong ; Zhao, Xiansheng ; Xu, Weihong ; Chen, Yuanyuan ; He, Qiuyu ; Wang, Lei ; Kong, Xiangzhen ; Qian, Feng ; Shi, Xiangguang ; Li, Pengcheng ; Ma, Yanyun ; Huang, Yan ; Jiang, Shuai ; Pu, Weilin ; Huang, Delin ; Wang, Jiucun ; Sun, Dayan ; Liu, Qingmei ; Tu, Wenzhen ; Zhao, Yinhuan ; Wu, Wenyu ; Shui, Xiaochuan ; Wu, Fei ; Zhu, Qing

AbstractObjectivesInnate immunity significantly contributes to SSc pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc.MethodsThe expression of TLR8 was analysed, based on a public dataset, and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model.ResultsTLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1β, COL I, COL III and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo.ConclusionTLR8 might be a promising therapeutic target for improving the treatment strategy for skin inflammation and fibrosis in SSc.

24 Nov 2023·Journal of Biomolecular Structure and Dynamics

Identification of new potent agonists for toll-like receptor 8 by virtual screening methods, molecular dynamics simulation, and MM-GBSA

Article

Author: Sadeghkhani, Farideh ; Hajihassan, Zahra ; Gharaghani, Sajjad

Toll-like receptor 8 (TLR8), as an endosomal transmembrane receptor, plays a crucial role in the innate immune response to neoplasia and viruses. Previous studies have shown that TLR8 agonists e.g. Motolimod can be used to treat patients with last-stage cancer. In this study, in order to find new suitable ligands for TLR8, 16 PBD codes related to TLR8 complexes were collected to design the pharmacophore models using the Pharmit server. Then the PubChem, and ZINC databases were screened by them. Subsequently, the ADME-Tox features of the compounds were detected using FAF-Drugs4 and the selected compounds were docked to TLR8 (PDB: 3w3j). Molecular dynamics simulation was used to compare compounds with the best docking scores, with Motolimod in complex with TLR8. Finally, two compounds were identified, PubChem: 124126919 (A) and PubChem: 18559540 (B), each with advantages over Motolimod. As the RMSD results showed that compound A has very good flexibility, in terms of energy calculated using the MM-GBSA method, complex B and TLR8 showed the lowest energy level compared to the rest of the complexes. These observations suggest that these two compounds could be used as TLR8 agonists with the desired pharmacological features in future experimental studies.Communicated by Ramaswamy H. Sarma.

01 Jul 2023·Biomedicine & Pharmacotherapy

TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia

Article

Author: Li, Yunlei ; Xie, Xina ; Liu, Linjiang ; Zhu, Yuqi ; Min, Shasha ; Sun, Changqing ; Li, Zesong ; Yang, Wei ; Li, Shi ; Huang, Xiaoru ; Xu, Ying ; Liu, Shuai ; Sun, Xiongfei ; Yan, Jie ; Mao, Longyi ; Zhang, Yu ; Liu, Kaiqing ; Xu, Kui

The clinical treatment of AML is dominated by "7 + 3" therapy, but it often shows great toxicity and limited therapeutic efficacy in application. Therefore, it is urgent to develop novel therapeutic strategies to achieve safe and efficient treatment of AML. Small-molecule inhibitors have the characteristics of high specificity, low off-target toxicity and remarkable therapeutic effect, and are receiving more and more attention in tumor therapy. In this study, we screened a library of 1972 FDA-approved small molecular compounds for those that induced the inflammatory death of AML cells, among which the TLR8 agonist Motolimod (MTL) showed stronger anti-AML activity in the animal model but slight affection on normal lymphocytes in control mice. In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation.

100 Deals associated with Motolimod

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External Link

KEGG	Wiki	ATC	Drug Bank
D10716	Motolimod	-	DB12303

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Head and Neck Neoplasms	Phase 2	-	Array BioPharma, Inc.	-
Ovarian Cancer	Phase 2	-	Array BioPharma, Inc.	-
Peritoneal Neoplasms	Phase 2	-	Array BioPharma, Inc.	-
Recurrent Platinum-Resistant Ovarian Carcinoma	Preclinical	CH	Celgene Corp.	02 Dec 2015
Squamous cell carcinoma of head and neck metastatic	Preclinical	US	Celgene Corp.	14 Oct 2013
Fallopian Tube Carcinoma	Preclinical	US	Celgene Corp.	31 Oct 2012
Ovarian Epithelial Carcinoma	Preclinical	US	Celgene Corp.	31 Oct 2012
Primary peritoneal carcinoma	Preclinical	US	Celgene Corp.	31 Oct 2012
Recurrent Primary Peritoneal Carcinoma	Preclinical	US	Celgene Corp.	31 Oct 2012
B-Cell Lymphoma	Discovery	US	Celgene Corp.	01 Jul 2011

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01836029 (Active8, CTgov)	Phase 2	Squamous cell carcinoma of head and neck metastatic	195	Carboplatin+cisplatin+VTX-2337+5-fluorouracil (Chemotherapy and Cetuximab Plus VTX-2337)	qadbnvcogw(gxtheiyigd) = xwaviabzzn pnttjaoafx (gxufnmtnop, yitkohqamn - renjclbavr) View more	-	29 Oct 2019
				Placebo+Carboplatin+cisplatin+5-fluorouracil (Chemotherapy and Cetuximab Plus Placebo)	qadbnvcogw(gxtheiyigd) = itqwyffwpa pnttjaoafx (gxufnmtnop, vylzfsvuxh - ffevwpvvwy) View more
NCT01666444 (Celgene, CTgov)	Phase 2	Primary peritoneal carcinoma \| Recurrent Primary Peritoneal Carcinoma \| Ovarian Epithelial Carcinoma \| Fallopian Tube Carcinoma	297	Placebo+Pegylated Liposomal Doxorubicin (PLD) (Pegylated Liposomal Doxorubicin (PLD) + Placebo)	vutqnddtnc(bjoucstaki) = buthpvpbmv jdjevwefbb (ldfwszylzd, sbzaxqmlqo - zpcemtlndk) View more	-	26 Sep 2019
				Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) (Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX))	vutqnddtnc(bjoucstaki) = ehhicdequx jdjevwefbb (ldfwszylzd, srpprismpy - cyrmdhcqrm) View more
NCT02431559 (CTgov)	Phase 1/2	Recurrent Platinum-Resistant Ovarian Carcinoma	53	Durvalumab+Pegylated Liposomal Doxorubicin+Motolimod (Phase 1, Dose Level 0a)	dudnlghajs(inbrhtbeoe) = mvwubxuxzm tclhljlpom (vgdaehwtlp, sosicomzoj - fbdiqcpisa) View more	-	23 Sep 2019
				Durvalumab+Pegylated Liposomal Doxorubicin+Motolimod (Phase 1, Dose Level 0b)	dudnlghajs(inbrhtbeoe) = ynkcwwvilu tclhljlpom (vgdaehwtlp, odmzsfinng - zjmjoyhvsn) View more
NCT01836029 (Active8, Pubmed) Manual	Phase 2	Squamous Cell Carcinoma of Head and Neck	195	Chemotherapy+cetuximab+Motolimod	(oziittvwqf) = rrodzoixui zwwnxadhqb (ooamrxcifh ) View more	Negative	01 Nov 2018
				Chemotherapy+cetuximab+Placebo	(oziittvwqf) = pcglruwxry zwwnxadhqb (ooamrxcifh ) View more
NCT01666444 (Celgene, Pubmed \| Ann Oncol) Manual	Phase 2	Ovarian Cancer	-	pegylated liposomal doxorubicin+motolimod	(nwhpndvnrb): HR = 1.22, P-Value = 0.923 View more	Positive	01 May 2017
				pegylated liposomal doxorubicin+Placebo
AAAAI2011	Not Applicable	Congestion of nasal mucosa	5	VTX-378 100 μg/dog	(foeyeatzsy) = ahygrgityf notdcopxxu (ecaavvkvrl )	-	01 Feb 2011
				VTX-378 500 μg/dog	(foeyeatzsy) = rpsjdwhohw notdcopxxu (ecaavvkvrl )