The purpose of this Phase 2 portion of the study is to use the dose and schedule of RX-5902 identified in the phase 1 to treat subjects with triple negative breast cancer.

Start Date01 Aug 2013

Sponsor / Collaborator

Rexahn Pharmaceuticals, Inc.

100 Clinical Results associated with RX-5902

100 Translational Medicine associated with RX-5902

100 Patents (Medical) associated with RX-5902

Literatures (Medical) associated with RX-5902

01 Dec 2020·BMC CancerQ2 · MEDICINE

RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer

Q2 · MEDICINE

ArticleOA

Author: Lang, Julie ; Hartman, Sarah J ; Pelanda, Roberta ; Eckhardt, S Gail ; Eisen, Andrew ; Benaim, Ely ; Bagby, Stacey M ; Diamond, Jennifer R ; Capasso, Anna ; Tentler, John J ; Lee, Young B ; Pitts, Todd M ; Yacob, Betelehem W ; Gittleman, Brian ; Kim, Deog Joong

AbstractBackgroundTriple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.MethodsTreatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2nullIl2rγnullSIRPαNOD (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells.ResultsThe addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01).ConclusionsConclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.

01 Nov 2019·Molecular Cancer TherapeuticsQ2 · MEDICINE

First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer

Q2 · MEDICINE

Article

Author: Hartman, Sarah J. ; Ionkina, Anastasia ; Benaim, Ely ; Yacob, Betelehem W. ; Gittleman, Brian ; Dailey, Kyrie L. ; George, Christina ; Eckhardt, S. Gail ; Lee, Young B. ; Tan, Aik Choon ; Capasso, Anna ; Kim, Deog Joong ; Bagby, Stacey M. ; Pitts, Todd M. ; Tentler, John J. ; Frank, Julie G. ; Currimjee, Naomi ; Kim, Jihye ; Diamond, Jennifer R.

AbstractRX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in vivo in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity in vitro against TNBC cell lines with an average IC50 of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G2–M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active in vivo against TNBC PDX models, and treatment resulted in a decrease in nuclear β-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFβ, and Wnt/β-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against in vitro and in vivo preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.

01 Dec 2018·Progress in Biophysics and Molecular Biology

Structural characterization of β-catenin and RX-5902 binding to phospho-p68 RNA helicase by molecular dynamics simulation

Article

Author: Ali, Waqar ; Rashid, Sajid ; Shafique, Shagufta

Emerging implications of probable ATP-dependent RNA helicase p68 in tumorigenesis and progression makes it a discerning target for cancer therapy. Recently it has been reported that tyrosyl-phosphorylation of p68 promotes β-catenin nuclear translocation and cancer metastasis through elevating the epithelial-mesenchymal transition. Despite recent advances, the structural characterization of this interaction, mode of action and induced conformational changes remain elusive. Here, through comparative structure analysis and molecular dynamics simulation assays, we explored comparative binding pattern of phospho-p68 against β-catenin. Conversely, due to the promising therapeutic potential of p68 in blocking the invasiveness and metastasis of cancer cells, we investigated the binding of heterocyclic N-substituted piperazine derivative-RX-5902 that inhibits the binding of phospho-p68 and β-catenin. Evidently, transactivation and C-terminal helicase domains of phospho-p68 exhibited dramatic conformational alterations to assist β-catenin and RX-5902 binding. As compared to unbound phospho-p68 (56.1 Å), the residual distances between transactivation domain-Ser79 and C-terminal helicase domain-Gln555 were reduced to 34.1 Å and 31 Å upon binding to β-catenin and RX-5902, respectively. In contrast, helicase ATP-binding domain remained conformationally stable throughout simulations. Clearly, the comparative docking-for-functional analysis of phospho-p68 against RX-5902 and β-catenin uncovered a spectrum of structural linkages associated with the molecular basis of β-catenin-dependent ATPase activity. Thus the outcomes of this study may provide a platform for the rational design of specific and potent inhibitors against phospho-p68 with a special emphasis on anticancer activity.

100 Deals associated with RX-5902

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 2	-	Rexahn Pharmaceuticals, Inc.	-
Advanced Malignant Solid Neoplasm	Preclinical	US	Rexahn Pharmaceuticals, Inc.	01 Aug 2013
Triple Negative Breast Cancer	Preclinical	US	Rexahn Pharmaceuticals, Inc.	01 Aug 2013
Melanoma	Preclinical	US	Rexahn Pharmaceuticals, Inc.	-
Pancreatic Cancer	Preclinical	US	Rexahn Pharmaceuticals, Inc.	-
Renal Cell Carcinoma	Preclinical	US	Rexahn Pharmaceuticals, Inc.	-

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