Delving into the Latest Updates on MBQ-167 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

CDC42

Action

inhibitors

Mechanism

CDC42 inhibitors(Cell division control protein 42 homolog inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal Diseases

Active Indication

Advanced breast cancerBreast Cancer

Inactive Indication-

Originator Organization

University of Puerto Rico-RÃo Piedras

Active Organization

University of Puerto Rico-RÃo Piedras

MBQ PHARMA INC.Startup

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC22H18N4

InChIKeyLJCANTASZGYJLG-UHFFFAOYSA-N

CAS Registry2097938-73-1

AbstractTriple negative breast cancer (TNBC) represents a therapeutic challenge in which standard chemotherapy is limited to paclitaxel. MBQ167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ167 in combination with paclitaxel in TNBC preclinical models, as a prelude to safety trials of this combination in patients with advanced breast cancer. Individual MBQ167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared with paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB231 and MDA-MB468), individual MBQ167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, whereas MBQ167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ167 and paclitaxel decreased established lung metastases by ∼80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ167 and paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.

01 Jun 2024·Translational Oncology

Efficacy and delivery strategies of the dual Rac/Cdc42 inhibitor MBQ-167 in HER2 overexpressing breast cancer

Article

Author: Rivera-Robles, Michael ; Velázquez-Vega, Luis E ; Grafals-Ruiz, Nilmary ; Vlaar, Cornelis P ; Cruz-Collazo, Ailed M ; Sánchez-Álvarez, Annelis O ; Dharmawardhane, Suranganie ; Dorta-Estremera, Stephanie ; Aponte-Reyes, Miciely ; Hernández-O'Farrill, Eliud ; Vivas-Mejía, Pablo E

Trastuzumab and trastuzumab-based treatments are the standard of care for breast cancer patients who overexpress the human epidermal growth factor receptor 2 (HER2). However, patients often develop resistance to trastuzumab via signaling from alternative growth factor receptors that converge to activate guanine nucleotide exchange factors (GEFs) that in turn activate the Rho GTPases Rac and Cdc42. Since Rac and Cdc42 have been implicated in high tumor grade and therapy resistance, inhibiting the activity of Rac and Cdc42 is a rational strategy to overcome HER2-targeted therapy resistance. Therefore, our group developed MBQ-167, a dual Rac/Cdc42 inhibitor with IC₅₀s of 103 nM and 78 nM for Rac and Cdc42, respectively, which is highly effective in reducing cell and tumor growth and metastasis in breast cancer cell and mouse models. Herein, we created a trastuzumab resistant variant of the SKBR3 HER2 positive breast cancer cell line and show that Rac activation is a central mechanism in trastuzumab resistance. Next, we tested the potential of targeting MBQ-167 to HER2 overexpressing trastuzumab-resistant cell lines in vitro, and show that MBQ-167, but not trastuzumab, reduces cell viability and induces apoptosis. When MBQ-167 was targeted to mammary fatpad tumors established from HER2 overexpressing cells via immunoliposomes functionalized with trastuzumab, MBQ-167 and MBQ-167-loaded liposomes show equal efficacy in reducing the viability of trastuzumab-resistant cells, inhibiting tumor growth in mouse xenografts, and reducing metastasis to lungs and liver. This study demonstrates the efficacy of MBQ-167 as an alternative therapeutic in HER2 overexpressing cancers, delivered either in free form or in liposomes.

01 Apr 2024·Life Sciences

Implication of Rac1 GTPase in molecular and cellular mitochondrial functions

Review

Author: Bailly, Christian ; Kluza, Jérôme ; Degand, Claire ; Laine, William ; Sauzeau, Vincent

Rac1 is a member of the Rho GTPase family which plays major roles in cell mobility, polarity and migration, as a fundamental regulator of actin cytoskeleton. Signal transduction by Rac1 occurs through interaction with multiple effector proteins, and its activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). The small protein is mainly anchored to the inner side of the plasma membrane but it can be found in endocellular compartments, notably endosomes and cell nuclei. The protein localizes also into mitochondria where it contributes to the regulation of mitochondrial dynamics, including both mitobiogenesis and mitophagy, in addition to signaling processes via different protein partners, such as the proapoptotic protein Bcl-2 and chaperone sigma-1 receptor (σ-1R). The mitochondrial form of Rac1 (mtRac1) has been understudied thus far, but it is as essential as the nuclear or plasma membrane forms, via its implication in regulation of oxidative stress and DNA damages. Rac1 is subject to diverse post-translational modifications, notably to a geranylgeranylation which contributes importantly to its mitochondrial import and its anchorage to mitochondrial membranes. In addition, Rac1 contributes to the mitochondrial translocation of other proteins, such as p53. The mitochondrial localization and functions of Rac1 are discussed here, notably in the context of human diseases such as cancers. Inhibitors of Rac1 have been identified (NSC-23766, EHT-1864) and some are being developed for the treatment of cancer (MBQ-167) or central nervous system diseases (JK-50561). Their effects on mtRac1 warrant further investigations. An overview of mtRac1 is provided here.

100 Deals associated with MBQ-167

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Advanced breast cancer	Phase 1	United States	MBQ PHARMA INC.Startup	09 Nov 2023
Advanced breast cancer	Phase 1	Puerto Rico	MBQ PHARMA INC.Startup	09 Nov 2023
Breast Cancer	Preclinical	-	University of Puerto Rico-RÃo Piedras	-

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


P2-01-05 (SABCS2023)	Not Applicable	Triple Negative Breast Cancer Adjuvant PR \| HER2 \| Rac ... View more	-	MBQ-167	hnqkowwxdb(otqspspmnu) = PXL treatment increased metastasis to the lungs and liver, while MBQ-167 prevented lung and liver metastases and reduced PXL-induced metastasis uhevepugcz (zpxstvyuyi ) View more	-	01 Mar 2023