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Neoplasms

Immune System Diseases

Respiratory Diseases

Small molecule drug

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Disease Domain	Count

Neoplasms	2
Immune System Diseases	2

Top 5 Drug Type	Count

Small molecule drug	2

Top 5 Target	Count

STAT(STAT transcription factors)	1
vimentin	1

BACKGROUNDVimentin, an intermediate filament protein, crucially contributes to the pathogenesis of inflammatory bowel disease (IBD) by interacting with genetic risk factors, facilitating pathogen infection, and modulating both innate and adaptive immune responses. This study aimed to demonstrate preclinical proof-of-concept for targeting vimentin therapeutically in IBD across diverse etiologies.METHODSThe small molecule compound ALD-R491 was assessed for vimentin binding using microscale thermophoresis, off-target effects via Eurofins screening, and therapeutic effects in mice with dextran sulfate sodium (DSS)-induced acute colitis and in IL-10 KO with spontaneous colitis. Parameters measured included body weight, survival, disease activity, colon length, and histology. The study analyzed intestinal proinflammatory cytokines, Th17/Treg cells, and epithelial barrier molecules, along with gut microbiota profiling.RESULTSALD-R491 specifically bound vimentin with a dissociation constant (KD) of 328 ± 12.66 nM and no off-target effects. In the DSS model, orally administered ALD-R491 exhibited dose-dependent therapeutic effects, superior to 5-ASA and Tofacitinib. In the IL-10 KO model, ALD-R491 significantly delayed colitis onset and progression, with near-zero disease activity index scores over a 15-week treatment. ALD-R491 consistently showed in both models a reduced proinflammatory cytokine expression, including TNF-α, IL-1β, IL-6, IL-17, IL-22, a rebalanced Th17/Treg axis by reducing RORγt while enhancing FoxP3 expression, and an improved epithelial barrier integrity by increasing intestinal expressions of Mucin-2, ZO-1 and Claudin5. The intestinal dysbiosis was restored with enriched presence of probiotics.CONCLUSIONSTargeting vimentin exhibits significant therapeutic effects on various facets of IBD pathogenesis, representing a compelling approach for the development of highly effective treatments in IBD.

26 Oct 2021·mBio

A Vimentin-Targeting Oral Compound with Host-Directed Antiviral and Anti-Inflammatory Actions Addresses Multiple Features of COVID-19 and Related Diseases

Article

Author: Yuan, Baoshi ; Sho, Eiketsu ; Liu, Zhiwei ; Wu, Jianping ; Wang, Tao ; Dong, Yingying ; Zhou, Fei ; Zhou, Ji ; Zhang, Jingping ; Symmes, Deebie ; Qu, Zhipeng ; Mo, Lian ; Chen, Ruihuan ; Huang, Kai ; Gu, Jingliang ; Chen, Jiqiao ; Wu, Wanchen ; Li, Zhizhen ; Xu, Ying

With the Delta variant currently fueling a resurgence of new infections in the fully vaccinated population, developing an effective therapeutic drug is especially critical and urgent in fighting COVID-19. In contrast to the many efforts to repurpose existing drugs or address only one aspect of COVID-19, we are developing a novel agent with first-in-class mechanisms of action that address both the viral infection and the overactive immune system in the pathogenesis of the disease.

15 Mar 2021·Clinical Cancer Research

Abstract P35: Targeting vimentin impacts multiple cellular processes, blocks the spike protein-ACE2-mediated pseudoviral infection in vitro and reduces the symptom and lung injury in aged mice with mouse-adapted SARS-CoV-2 infection in vivo

Author: Wu, Jianping ; Zhou, Fei ; Dinnon, Kenneth ; Graham, Rachel ; Chen, Ruihuan ; Yuan, Baoshi ; Mo, Lian ; Gully, Kendra ; Dong, Yingying ; Xu, Ying ; Li, Zhizhen ; Baric, Ralph

AbstractVimentin intermediate filament is involved in multiple steps of viral infection such as viral entry, trafficking and egress, as well as in various mechanisms of hyperinflammation such as the restraint of Treg cell functions and the activation of NLRP3 inflammasome. We evaluated a vimentin-binding small molecule compound ALD-R491 for its effects on cellular processes related to viral infection and for its efficacy in treating SARS-CoV2 infection in vitro and in vivo. In cultured cells, the compound could reduce endocytosis by 10%, endosomal trafficking by 40% and exosomal release by over 30%. In an infection system consisting of a lentiviral pseudotype bearing the SARS-CoV-2 spike protein and HEK293 cells over-expressing the human ACE2 receptor with multiplicity of infection (MOI) of 1, 10 and 100, the compound inhibited the infection up to a maximum of over 90%, with IC50 < 50 nM, CC50 > 10 μM, and SI > 200. After oral administration of ALD-R491 in rats, the plasma concentration of the compound reached the peak (Tmax) at around 5 h with a half-life (T1/2) of about 5 h. The compound was widely distributed and enriched in tissues in vivo in rats with a volume of distribution (Vd) of over 2,000 ml/kg. The lung and the lymph nodes were among the tissues with high drug exposures. In rats receiving oral gavage of the compound at 30 mg/kg, the drug exposure in the lung and the lymph nodes maintained at levels over 1 μM from 1 h to 6 h after the oral dosing. In the syngeneic mouse tumor CT26 model, ALD-R491 was found to activate regulatory T cells (Tregs) in vivo and enhance de novo generation of Tregs in lymph nodes of the mice. In the Mouse-Adapted SARS-CoV2 model, aged mice (11-12 months) were used to provide a harder test of recovery from infection that reflects the severeness of COVID-19 in old patients. For therapeutic treatment, the mice were orally administered with the compound 24 h after the SARS-CoV2 infection once per day on Day 1, Day 2 and Day 4. At 10 mg/kg, ALD-R491 significantly reduced the body weight loss of the mice (p<0.01 on Day 5 post-infection). At both 3 mg/kg and 10 mg/kg, the compound significantly reduced the hemorrhagic score for the lungs (p<0.01 and p<0.05, respectively, on Day 5). These results indicate that vimentin intermediate filament is an effective host-directed antiviral target. Importantly, the vimentin-binding small molecule ALD-R491 impacts multiple aspects of SARS-CoV2 infection, has a favorable oral pharmacokinetics and a wide therapeutic window, and therefore may be a promising therapeutic candidate for treating COVID-19. Statement: Aluda Pharmaceuticals, Inc. has utilized the non-clinical and pre-clinical services program offered by the National Institute of Allergy and Infectious Diseases.Citation Format: Zhizhen Li, Jianping Wu, Baoshi Yuan, Kenneth Dinnon, III, Lian Mo, Fei Zhou, Yingying Dong, Kendra Gully, Ralph Baric, Rachel Graham, Ying Xu, Ruihuan Chen. Targeting vimentin impacts multiple cellular processes, blocks the spike protein-ACE2-mediated pseudoviral infection in vitro and reduces the symptom and lung injury in aged mice with mouse-adapted SARS-CoV-2 infection in vivo [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P35.

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Pipeline

Pipeline Snapshot as of 08 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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