Delving into the Latest Updates on CBL-0137 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [3]

Target

FACT x NF-κB x YAP1 x p53

Mechanism

FACT antagonists(SPT16 homolog, facilitates chromatin remodeling subunit antagonists), NF-κB modulators(Nuclear factor NF-kappa-B complex modulators), YAP1 inhibitors(Yes1 associated transcriptional regulator inhibitors)

+ [1]

Therapeutic Areas

NeoplasmsImmune System DiseasesNervous System Diseases+ [4]

Active Indication

Diffuse Intrinsic Pontine GliomaDiffuse midline glioma, point mutation K27M in histone H3Osteosarcoma, Recurrent+ [6]

Inactive Indication

Advanced Malignant Solid NeoplasmGlioblastomaMelanoma recurrent+ [2]

Originator Organization

Cleveland BioLabs, Inc.

Active Organization

Incuron LLCIncuron LLC (US)

Inactive Organization

Roswell Park Comprehensive Cancer Center

Drug Highest PhasePhase 1/2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC21H24N2O2

InChIKeyJKCSODVERGVDLT-UHFFFAOYSA-N

CAS Registry1197996-80-7

View All Structures (2)

Phase I, open label, dose-escalation, and safety study designed to assess the safety and biologic activity of the investigational agent CBL0137 in combination with standard of care drugs, ipilimumab and nivolumab in sequential cohorts of adult patients with locally advanced and metastatic melanoma who are candidates for immune checkpoint blockade and have tumors accessible for serial biopsies.

Start Date30 Nov 2022

Sponsor / Collaborator

The Fox Chase Cancer Center

[+1]

NCT04870944 / RecruitingPhase 1/2IIT

A Phase 1/2 Trial of CBL0137 (NSC# 825802) in Patients With Relapsed or Refractory Solid Tumors Including CNS Tumors and Lymphoma

This phase I/II trial evaluates the best dose, side effects and possible benefit of CBL0137 in treating patients with solid tumors, including central nervous system (CNS) tumors or lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Drugs, such as CBL0137, block signals passed from one molecule to another inside a cell. Blocking these signals can affect many functions of the cell, including cell division and cell death, and may kill cancer cells.

Start Date28 Jan 2022

Sponsor / Collaborator

The Children's Oncology Group Foundation, Inc.

[+2]

NCT03727789 / TerminatedPhase 1IIT

A Single-Center Phase I Dose Escalation/Response Trial to Evaluate Safety, Tolerability, and Anti-Tumor Efficacy of Intra-Arterial CBL0137 for Patients With Advanced Extremity Melanoma or Sarcoma

This phase I trial studies best dose and side effects of CBL0137 in treating patients with extremity melanoma or sarcoma that has spread to other places in the body. Drugs, such as CBL0137, may work by binding to tumor cell deoxyribonucleic acid (DNA) to stop the cell from growing further.

Start Date01 Jul 2019

Sponsor / Collaborator

Roswell Park Comprehensive Cancer Center

[+1]

100 Clinical Results associated with CBL-0137

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100 Translational Medicine associated with CBL-0137

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100 Patents (Medical) associated with CBL-0137

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59

Literatures (Medical) associated with CBL-0137

20 Aug 2024·Journal of Virology

Impact of the interaction between herpes simplex virus 1 ICP22 and FACT on viral gene expression and pathogenesis

Article

Author: Kato, Akihisa ; Koyanagi, Naoto ; Maruzuru, Yuhei ; Liu, Shaocong ; Kawaguchi, Yasushi ; Takeshima, Kosuke

ABSTRACTFacilitates chromatin transcription (FACT) interacts with nucleosomes to promote gene transcription by regulating the dissociation and reassembly of nucleosomes downstream and upstream of RNA polymerase II (Pol II). A previous study reported that herpes simplex virus 1 (HSV-1) regulatory protein ICP22 interacted with FACT and was required for its recruitment to the viral DNA genome in HSV-1-infected cells. However, the biological importance of interactions between ICP22 and FACT in relation to HSV-1 infection is unclear. Here, we mapped the minimal domain of ICP22 required for its efficient interaction with FACT to a cluster of five basic amino acids in ICP22. A recombinant virus harboring alanine substitutions in this identified cluster led to the decreased accumulation of viral mRNAs from UL54, UL38, and UL44 genes, reduced Pol II occupancy of these genes in MRC-5 cells, and impaired HSV-1 virulence in mice following ocular or intracranial infection. Furthermore, the treatment of mice infected with wild-type HSV-1 with CBL0137, a FACT inhibitor currently being investigated in clinical trials, significantly improved the survival rate of mice. These results suggested that the interaction between ICP22 and FACT was required for efficient HSV-1 gene expression and pathogenicity. Therefore, FACT might be a potential therapeutic target for HSV-1 infection.IMPORTANCEICP22 is a well-known regulatory factor of HSV-1 gene expression, but its mechanism(s) are poorly understood. Although the interaction of FACT with ICP22 was reported previously, its significance in HSV-1 infection is unknown. Given that FACT is involved in gene transcription, it is of interest to investigate this interaction as it relates to HSV-1 gene expression. To determine a direct link between the interaction and HSV-1 infection, we mapped a minimal domain of ICP22 required for its efficient interaction with FACT and generated a recombinant virus carrying mutations in the identified domain. Using the recombinant virus, we obtained evidence suggesting that the interaction between ICP22 and FACT promoted Pol II transcription from HSV-1 genes and viral virulence in mice. In addition, CBL0137, an inhibitor of FACT, effectively protected mice from lethal HSV-1 infection, suggesting FACT might be a potential target for the development of novel anti-HSV drugs.

05 Aug 2024·Frontiers in Bioscience-Landmark

Anticancer Plant Secondary Metabolites Induce Linker Histone Depletion from Chromatin

Article

Author: Jordan, Albert ; Antonova, Irina ; Safina, Alfiya ; Belitsky, Gennady ; Yakubovskaya, Marianna ; Zabotina, Tatiana ; Borunova, Anna ; Vlasova, Olga ; Gudkov, Andrei ; Gurova, Katerina ; Zenkov, Roman ; García-Gomis, Daniel ; Kirsanov, Kirill ; Naberezhnov, Denis

BACKGROUNDMany plant secondary metabolites (PSMs) were shown to intercalate into DNA helix or interact with DNA grooves. This may influence histone-DNA interactions changeing chromatin structure and genome functioning.METHODSNucleosome stability and linker histone H1.2, H1.4 and H1.5 localizations were studied in HeLa cells after the treatment with 15 PSMs, which are DNA-binders and possess anticancer activity according to published data. Chromatin remodeler CBL0137 was used as a control. Effects of PSMs were studied using fluorescent microscopy, flowcytometry, quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR), western-blotting.RESULTSWe showed that 1-hour treatment with CBL0137 strongly inhibited DNA synthesis and caused intensive linker histone depletion consistent with nucleosome destabilization. None of PSMs caused nucleosome destabilization, while most of them demonstrated significant influence on linker histone localizations. In particular, cell treatment with 11 PSMs at non-toxic concentrations induced significant translocation of the histone H1.5 to nucleoli and most of PSMs caused depletion of the histones H1.2 and H1.4 from chromatin fraction. Curcumin, resveratrol, berberine, naringenin, and quercetin caused significant redistribution of all three variants of the studied linker histones showing some overlap of PSM effects on linker histone DNA-binding. We demonstrated that PSMs, which induced the most significant redistribution of the histone H1.5 (berberine, curcumin and naringenin), influence the proportion of cells synthesizing DNA, expressing or non-expressing cyclin B and influence cell cycle distribution. Berberine induction of H1.5 translocations to nucleoli was shown to occur independently on the phases of cell cycle (metaphase was not analyzed).CONCLUSIONSFor the first time we revealed PSM influence on linker histone location in cell nuclei that opens a new direction of PSM research as anticancer agents.

01 Jul 2024·Advanced Materials

Manipulating Radiation‐Sensitive Z‐DNA Conformation for Enhanced Radiotherapy

Article

Author: Wang, Xue ; Zhang, Jie ; Wang, Dongmei ; Gu, Chenglu ; Hou, Lingmi ; Liao, You ; Zheng, Ziye ; Guo, Xihong ; Zhu, Shuang ; Zhang, Fuquan ; Sun, Baoyun ; Zeng, Hao ; Gu, Zhanjun ; Yan, Junfang

AbstractDNA double‐strand breaks (DSBs) yield highly determines radiotherapy efficacy. However, improving the inherent radiosensitivity of tumor DNA to promote radiation‐induced DSBs remains a challenge. Using theoretical and experimental models, the underexplored impact of Z‐DNA conformations on radiosensitivity, yielding higher DSBs than other DNA conformations, is discovered. Thereout, a radiosensitization strategy focused on inducing Z‐DNA conformation, utilizing CBL@HfO2 nanocapsules loaded with a Z‐DNA inducer CBL0137, is proposed. A hollow mesoporous HfO2 (HM‐HfO2) acts as a delivery and an energy depositor to promote Z‐DNA breakage. The nanocapsule permits the smart DSBs accelerator that triggers its radiosensitization with irradiation stimulation. Impressively, the CBL@HfO2 facilitates the B‐Z DNA conformational transition, augmenting DSBs about threefold stronger than irradiation alone, generating significant tumor suppression with a 30% cure rate. The approach enables DSBs augmentation by improving the inherent radiosensitivity of DNA. As such, it opens up an era of Z‐DNA conformation manipulation in radiotherapy.

100 Deals associated with CBL-0137

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diffuse midline glioma, point mutation K27M in histone H3	Phase 2	AU	Incuron LLC	28 Jan 2022
Diffuse midline glioma, point mutation K27M in histone H3	Phase 2	US	Incuron LLC	28 Jan 2022
Recurrent Lymphoma	Phase 2	US	Incuron LLC	28 Jan 2022
Recurrent Lymphoma	Phase 2	AU	Incuron LLC	28 Jan 2022
Refractory Malignant Solid Neoplasm	Phase 2	AU	Incuron LLC	28 Jan 2022
Refractory Malignant Solid Neoplasm	Phase 2	US	Incuron LLC	28 Jan 2022
Refractory Osteosarcoma	Phase 2	US	Incuron LLC	28 Jan 2022
Refractory Osteosarcoma	Phase 2	AU	Incuron LLC	28 Jan 2022
Relapsed Solid Neoplasm	Phase 2	US	Incuron LLC	28 Jan 2022
Relapsed Solid Neoplasm	Phase 2	AU	Incuron LLC	28 Jan 2022

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01905228 (ASCO2020) Manual	Phase 1	Advanced Malignant Solid Neoplasm	83	CBL-0137	(adjcoeitfx) = eajmljxnfe twfkumpdgu (ovnnptqsdn ) View more	Positive	29 May 2020
847 (ASCO2020) Manual	Phase 1	Advanced Malignant Solid Neoplasm	60	CBL0137	(qmctuibozt) = tsylprbuxk fmfeywzlwr (bffsgpfkgc ) View more	Positive	25 May 2020
ESMO_GI2013	Not Applicable	Pancreatic Ductal Adenocarcinoma FACT-positive	5	Curaxin CBL0137 90 mg/kg	drapnqcnzg(nljccvnxtu) = ymggnyemau udzcbiymtw (cnjprdeggv )	Positive	03 Jul 2013