This is a phase 1/2 single arm study to determine the safety and efficacy of VLX1570 IV infusion administered with low dose dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.

Start Date08 Apr 2015

Sponsor / Collaborator

Vivolux AB

[+1]

100 Clinical Results associated with VLX-1570

100 Translational Medicine associated with VLX-1570

100 Patents (Medical) associated with VLX-1570

Literatures (Medical) associated with VLX-1570

16 Feb 2024·ACS Chemical Biology

Covalent Targeting As a Common Mechanism for Inhibiting NLRP3 Inflammasome Assembly

Article

Author: Melillo, Bruno ; Sun, Jie ; Cravatt, Benjamin F ; Kutseikin, Sergei ; Teijaro, John R ; Bollong, Michael J ; Nutsch, Kayla ; Nguyen, Thu ; Njomen, Evert ; Rosarda, Jessica D ; Stanton, Caroline ; Wiseman, R Luke ; Saez, Enrique ; Li-Ma, Chloris

The NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines, including IL-1β and IL-18. Aberrant overactivation of NLRP3 is implicated in numerous inflammatory disorders. However, the activation and regulation of NLRP3 inflammasome signaling remain poorly understood, limiting our ability to develop pharmacologic approaches to target this important inflammatory complex. Here, we developed and implemented a high-throughput screen to identify compounds that inhibit the inflammasome assembly and activity. From this screen, we identify and profile inflammasome inhibition of 20 new covalent compounds across nine different chemical scaffolds, as well as many known inflammasome covalent inhibitors. Intriguingly, our results indicate that NLRP3 possesses numerous reactive cysteines on multiple domains whose covalent targeting blocks the activation of this inflammatory complex. Specifically, focusing on compound VLX1570, which possesses multiple electrophilic moieties, we demonstrate that this compound allows covalent, intermolecular cross-linking of NLRP3 cysteines to inhibit inflammasome assembly. Our results, along with the recent identification of numerous covalent molecules that inhibit NLRP3 inflammasome activation, further support the continued development of electrophilic compounds that target reactive cysteine residues on NLRP3 to regulate its activation and activity.

01 Jan 2022·Journal of Cellular and Molecular MedicineQ2 · MEDICINE

VLX1570 regulates the proliferation and apoptosis of human lung cancer cells through modulating ER stress and the AKT pathway

Q2 · MEDICINE

ArticleOA

Author: Xu, Chenxin ; Ma, Rong ; Feng, Jifeng ; Wu, Jianzhong ; Lv, Yan ; Du, Yuxin ; Wang, Juan ; Du, Tongde ; Lu, Ya

AbstractThe ubiquitin‐proteasome system (UPS) possesses unique functions in tumorigenesis and has great potential for targeting tumours. The effectiveness of inhibitors targeting UPS in solid tumours remains to be studied. We screened a library of inhibitors targeting the ubiquitination system and found the highly potent, low‐concentration inhibitor molecule VLX1570 that specifically killed lung cancer cells. VLX1570 is an inhibitor of deubiquitinating enzyme activity and has also shown potential for preclinical cancer treatment. We found that VLX1570 significantly inhibited lung cancer cells proliferation and colony formation. VLX1570 induced a G2/M cell cycle arrest by downregulating CDK1 and CyclinB1. Moreover, VLX1570 significantly promoted the mitochondrial‐associated apoptosis. Mechanistically speaking, VLX1570 activated the PERK/IRE1/ATF6 pathway and induced ER stress in lung cancer cell lines. The inhibition of ER stress by tauroursodeoxycholic acid sodium or 4‐phenylbutyric acid enhanced VLX1570‐induced apoptosis. In addition, VLX1570 treatment led to the inactivation of Akt signalling and inhibited the proliferation of lung cancer cells by downregulating the Akt pathway. Moreover, combined treatment with VLX1570 and Afatinib or Gefitinib induced synergistic anti‐lung cancer activity. Our present study demonstrated a novel therapy using VLX1570, which inhibited the proliferation and increased apoptosis in human lung cancer.

01 Aug 2021·Cancer ScienceQ2 · MEDICINE

VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines

Q2 · MEDICINE

ArticleOA

Author: Nakahara, Takako ; Takeuchi, Masaki ; Kurozumi, Nami ; Kitanaka, Akira ; Sakakibara, Kanae ; Shibakura, Misako ; Tsujioka, Takayuki ; Suemori, Shin‐ichiro ; Tohyama, Kaoru ; Ouchida, Mamoru

AbstractA novel proteasome deubiquitinase inhibitor, VLX1570, has been highlighted as a promising therapeutic agent mainly for lymphoid neoplasms and solid tumors. We examined in vitro effects of VLX1570 on eight myeloid and three lymphoid leukemia cell lines. From cell culture studies, 10 out of 11 cell lines except K562 were found to be susceptible to VLX1570 treatment and it inhibited cell growth mainly by apoptosis. Next, to identify the signaling pathways associated with apoptosis, we performed gene expression profiling using HL‐60 with or without 50 nmol/L of VLX1570 for 3 hours and demonstrated that VLX1570 induced the genetic pathway involved in “heat shock transcription factor 1 (HSF1) activation”, “HSF1 dependent transactivation”, and “Regulation of HSF1 mediated heat shock response”. VLX1570 increased the amount of high molecular weight polyubiquitinated proteins and the expression of HSP70 as the result of the suppression of ubiquitin proteasome system, the expression of heme oxygenase‐1, and the amount of phosphorylation in JNK and p38 associated with the generation of reactive oxygen species (ROS) induced apoptosis and the amount of phosphorylation in eIF2α, inducing the expression of ATF4 and endoplasmic reticulum (ER) stress dependent apoptosis protein, CHOP, and the amount of phosphorylation slightly in IRE1α, leading to increased expression of XBP‐1s in leukemia cell lines. In the present study, we demonstrate that VLX1570 induces apoptosis and exerts a potential anti‐leukemic effect through the generation of ROS and induction of ER stress in leukemia cell lines.

100 Deals associated with VLX-1570

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Bone Marrow Neoplasms	Phase 2	US	Vivolux AB	08 Apr 2015
Multiple Myeloma	Phase 2	FI	Vivolux AB	-
Multiple Myeloma	Phase 2	FI	Vivolux AB	-
Waldenstrom Macroglobulinemia	Phase 2	US	-	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02372240 (Pubmed \| Invest New Drugs) Manual	Phase 1	Multiple Myeloma	14	VLX1570	igecleyvab(fibxbpowap) = Anti-myeloma effects were noted at doses at or above 0.6 mg/kg. kejxlsmjmk (avvygzdtcm ) View more	Negative	01 Oct 2020

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