Delving into the Latest Updates on ABD-3001 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

DIMATE

Target

ALDH1A1 x ALDH1A2

Action

inhibitors

Mechanism

ALDH1A1 inhibitors(aldehyde dehydrogenase 1 family member A1 inhibitors), ALDH1A2 inhibitors(aldehyde dehydrogenase 1 family member A2 inhibitors)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesRespiratory Diseases+ [2]

Active Indication

Recurrent Myelodysplastic SyndromeRefractory acute myeloid leukemiaRelapsing acute myeloid leukemia+ [5]

Inactive Indication-

Originator Organization

Advanced BioDesign SAS

Active Organization

Advanced BioDesign SASInstitute of Molecular Genetics of the ASCR vvi

First Faculty of Medicine, Charles University in Prague

Inactive Organization-

License Organization-

Drug Highest PhasePhase 1/2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC9H15NOS

InChIKeyXFLSMXBNQSTUIY-UHFFFAOYSA-N

CAS Registry350229-29-7

Author: Iglesias I Felip, Carmela ; Di Stefano, Barbara ; Costello, Regis ; Rebollido-Rios, Rocio ; Perez-Alea, Mileidys ; Sánchez-Redondo, Sara ; Penarroche-Díaz, Reinier ; Ceylan, Ismail ; Venton, Geoffroy ; González, Elena ; Fournet, Guy ; Martin, Guillaume ; Borroto Escuela, Dasiel Oscar ; Romero Fernández, Wilber

AbstractAldehyde dehydrogenases (ALDHs) are multifunctional enzymes that oxidize diverse endogenous and exogenous aldehydes. We conducted a meta-analysis based on The Cancer Genome Atlas and Gene Expression Omnibus data and detected genetic alterations in ALDH1A1, ALDH1A3, or ALDH3A1, 86% of which were gene amplification or mRNA upregulation, in 31% of nonsmall cell lung cancers (NSCLCs). The expression of these isoenzymes impacted chemoresistance and shortened survival times in patients. We hypothesized that these enzymes provide an oxidative advantage for the persistence of NSCLC. To test this hypothesis, we used genetic and pharmacological approaches with DIMATE, an irreversible inhibitor of ALDH1/3. DIMATE showed cytotoxicity in 73% of NSCLC cell lines tested and demonstrated antitumor activity in orthotopic xenografts via hydroxynonenal-protein adduct accumulation, GSTO1-mediated depletion of glutathione and increased H2O2. Consistent with this result, ALDH1/3 disruption synergized with ROS-inducing agents or glutathione synthesis inhibitors to trigger cell death. In lung cancer xenografts with high to moderate cisplatin resistance, combination treatment with DIMATE promoted strong synergistic responses with tumor regression. These results indicate that NSCLCs with increased expression of ALDH1A1, ALDH1A3, or ALDH3A1 may be targeted by strategies involving inhibitors of these isoenzymes as monotherapy or in combination with chemotherapy to overcome patient-specific drug resistance.

12 Oct 2017·OncogeneQ1 · MEDICINE

ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment

Q1 · MEDICINE

Article

Author: Martin, G ; Sánchez-Redondo, S ; Recio, J A ; Tenbaum, S ; Fournet, G ; Muñoz, E ; Ferrer, B ; Cortés, J ; Ceylan, I ; Hernandez-Losa, J ; Garcia-Patos, V ; Pérez-Alea, M ; McGrail, K ; Costello, R

Despite the promising targeted and immune-based interventions in melanoma treatment, long-lasting responses are limited. Melanoma cells present an aberrant redox state that leads to the production of toxic aldehydes that must be converted into less reactive molecules. Targeting the detoxification machinery constitutes a novel therapeutic avenue for melanoma. Here, using 56 cell lines representing nine different tumor types, we demonstrate that melanoma cells exhibit a strong correlation between reactive oxygen species amounts and aldehyde dehydrogenase 1 (ALDH1) activity. We found that ALDH1A3 is upregulated by epigenetic mechanisms in melanoma cells compared with normal melanocytes. Furthermore, it is highly expressed in a large percentage of human nevi and melanomas during melanocyte transformation, which is consistent with the data from the TCGA, CCLE and protein atlas databases. Melanoma treatment with the novel irreversible isoform-specific ALDH1 inhibitor [4-dimethylamino-4-methyl-pent-2-ynthioic acid-S methylester] di-methyl-ampal-thio-ester (DIMATE) or depletion of ALDH1A1 and/or ALDH1A3, promoted the accumulation of apoptogenic aldehydes leading to apoptosis and tumor growth inhibition in immunocompetent, immunosuppressed and patient-derived xenograft mouse models. Interestingly, DIMATE also targeted the slow cycling label-retaining tumor cell population containing the tumorigenic and chemoresistant cells. Our findings suggest that aldehyde detoxification is relevant metabolic mechanism in melanoma cells, which can be used as a novel approach for melanoma treatment.

01 Apr 2009·Current Medicinal ChemistryQ2 · MEDICINE

Synergetic Bitherapy in Mice with Xenografts of Human Prostate Cancer Using a Methional Mimic (METLICO) and an Aldehyde Dehydrogenase 3 Inhibitor (MATE): Systemic Intraperitoneal (IP) and Targeted Intra-Tumoral (IT) Administration

Q2 · MEDICINE

Article

Author: Hiltbrand, E. ; Morel, D. ; Mehier, H. ; Rochedix, M.-E. ; Chantepie, J. ; Fournet, G. ; Giliberto, J.-P. ; Quash, G. ; Paret, M.-J. ; Reichert, U. ; Gore, J.

An intraperitoneal (IP) monotherapy in nu/nu mice with subcutaneous xenografts of a human prostate epithelial cancer cell line:DU145 was undertaken with an aldehyde dehydrogenase 3 inhibitor MATE, that is a potent apoptogen on (DU145) in culture but not on their human prostate epithelial normal counterparts [13] . Tumour growth was slowed down but treatment had to be done 5days/week. To try to potentiate the action of MATE in vivo, a bitherapy was undertaken based on the synergetic apoptotic effect that had been observed previously in culture on DU145 treated with a methional mimic METLICO and DIMATE, an inhibitor of ALDH1 and ALDH3 [19]. The bitherapy with METLICO/MATE administered IP was as effective as the monotherapy with MATE alone by IP, but at a 2-fold lower dose of MATE and at a dose of METLICO that had no growth-inhibitory effect as a monotherapy . Hence there was definite synergism with bitherapy. To try to increase the efficacy of bitherapy, it was administered by the intra-tumoral (IT) route using the recently developed 20-bars-pressurized microinjection system from CERMA [16, 17]. IT administration of the bitherapy was indeed more effective than that by IP as regards tumour volumes are concerned. Histopathological analysis of IT-treated tumours confirmed that there were many necrotized zones but intact cells were still present. Approaches for treating a wider zone of tumour tissue by IT-bitherapy are discussed.

100 Deals associated with ABD-3001

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Recurrent Myelodysplastic Syndrome	Phase 2	France	Advanced BioDesign SAS	08 Nov 2022
Refractory acute myeloid leukemia	Phase 2	France	Advanced BioDesign SAS	08 Nov 2022
Relapsing acute myeloid leukemia	Phase 2	France	Advanced BioDesign SAS	08 Nov 2022
Acute Myeloid Leukemia	Preclinical	Czechia	First Faculty of Medicine, Charles University in Prague	08 Jun 2023
Acute Myeloid Leukemia	Preclinical	Czechia	Institute of Molecular Genetics of the ASCR vvi	08 Jun 2023
Breast Cancer	Preclinical	France	Advanced BioDesign SAS	-
Melanoma	Preclinical	France	Advanced BioDesign SAS	-
Non-Small Cell Lung Cancer	Preclinical	France	Advanced BioDesign SAS	-
Osteosarcoma	Preclinical	France	Advanced BioDesign SAS	-