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Natsar Pharmaceuticals is an applied research and drug development company focused on the development of novel treatments for cancer and other diseases. In our quest to characterize cellular pathways that are essential for the oncogenic state, we have focused on helicases which are dysregulated in many cancer types.
One such helicase is DDX3, which is overexpressed in many cancer types and has been associated with lower survival in lung cancer patients. We have synthesized a DDX3 inhibitor, RK‐33, which can potentially be used in cancer treatment. Binding of RK‐33 to DDX3 impedes the function of DDX3, resulting in activation of cell death pathways, inhibition of the Wnt‐signaling pathway, and abrogation of non‐homologous end‐joining (NHEJ) activity. In combination with radiation, synergistic cell death effects have been observed both in vitro and in multiple preclinical cancer models. We are currently moving this synthesized compound into clinical trials.
Professor, Johns Hopkins University, Founder & Director, NATSAR
ACTING CHIEF CLINICAL OFFICER
Based on our identification of an RNA helicase, DDX3, which is overexpressed in many cancer types and has been associated with lower survival in lung cancer patients, we have designed a first‐in‐class small molecule inhibitor, RK‐33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK‐33 causes G1 cell cycle arrest, induces apoptosis, and promotes radiation sensitization in DDX3‐overexpressing cells. Overall, inhibition of DDX3 by RK‐33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for cancer therapy.
DDX3 is a member of the DEAD‐box family which is involved in a number of cellular processes such as transcription, RNA splicing, mRNA export, and translation initiation (Lorsch, 2002; Rocak & Linder, 2004). DDX3 has also been associated with cancer biogenesis (Hu et al, 2004). We identified DDX3 in a microarray screen of breast cancer cells exposed to cigarette smoke and demonstrated its role in cancer progression (Botlagunta et al, 2008).
DDX3 promotes proliferation and cellular transformation (Hu et al, 2004; Shih et al, 2007; Lee et al, 2008), has anti‐apoptotic properties (Li et al, 2006; Sun et al, 2008, 2011), modulates cell adhesion and motility (Chen et al, 2014), and responds to hypoxia via HIF‐1α (Botlagunta et al, 2011; Bol et al, 2013).
Also, recent evidence has identified that DDX3 acts as an allosteric activator of casein kinase 1 in the Wnt/β‐catenin pathway (Cruciat et al, 2013). Initially, the Wnt/β‐catenin pathway was described in colon cancer. Activating mutations of DDX3 were also shown to be involved in pathogenic Wnt pathway activation in medulloblastoma (Jones et al, 2012; Pugh et al, 2012; Robinson et al, 2012) and chronic lymphatic leukemia (CLL) (Wang et al, 2011). Recently, it has been shown that activated Wnt signaling predicts decreased survival in lung cancer patients (Xu et al, 2011; Shapiro et al, 2013) and decreases sensitivity to radiation therapy (Woodward et al, 2007; Zhang et al, 2010).
RK‐33 binds to DDX3 and abrogates its activity, causing G1 cell cycle arrest, inducing apoptosis, and promoting radiation sensitization in DDX3‐overexpressing cells. Mechanistically, loss of DDX3 function either by shRNA or by RK‐33 impaired Wnt signaling through disruption of the DDX3–β‐catenin axis and inhibited non‐homologous end joining—the major DNA repair pathway in mammalian somatic cells. Inhibition of DDX3 by RK‐33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for cancer therapy. RK‐33 combined with radiation therapy has been shown to induce tumor regression in lung cancer models, with no toxicity at the therapeutic dose.
Our clinical development plan will include sarcoma and breast cancer. We will use a novel, biomarker-driven Phase I trial design. Enrollment will be limited to patients with DDX3 expression demonstrated on a pre-treatment tumor biopsy. Dose finding will be based on a Continual Reassessment Model, and there will be a sarcoma-only expansion cohort at the recommended Phase II dose to obtain preliminary evidence of efficacy, increased data on toxicity, and to allow pharmacodynamic and pharmacokinetic studies. Subsequent clinical development is planned in multiple solid tumors including prostate, and medulloblastoma, and in combination with radiation.
Read more about Natsar below.
A recent non-clinical study by Fimia et al. (Proteomic Analysis Identifies the RNA Helicase DDX3 as a Host Target Against SARS-CoV2 Infection) in the journal Antiviral Research adds further support to the role of DDX3 as a host target against SARS-CoV2 infection. The study also demonstrated that inhibition of DDX3 by RK-33 significantly reduced SARS-CoV-2 replication in cell culture.
January 2021 – A new review article “Targeting host DEAD-box RNA helicase DDX3X for treating viral infections” is published in Antiviral Research by Natsar's founder and Professor of Radiology and Oncology at Johns Hopkins School of Medicine, Dr. Venu Raman. Natsar’s small molecule, RK-33 has been demonstrated to effectively abrogate virion production in both + ssRNA (DENV, WNV, and ZIKA) and -ssRNA (RSV and hPIV-3) infections.
In pancreatic CSCs, PAF1 forms a sub-complex that regulates expression of genes that control stem cell features. Knockout of PAF1 reduced the ability of pancreatic tumors to develop and progress in mice and numbers of CSCs.
In this paper by Vellky et al. the authors have demonstrated that high DDX3 expression downregulates androgen receptor (AR) expression, leading to the generation of castration-resistant prostate cancer phenotypes. Interestingly, the authors showed that treatment with RK-33, both in vitro and in vivo, deregulates DDX3 expression, thus sensitizing the castration-resistant prostate cancer cells to AR-signaling inhibitors. Significance of this finding is that use of RK-33, in a clinical setting, for castration-resistant prostate cancer treatment is a strategy that can be exploited both to decrease the generation of castration-resistant prostate cancers as well as potentially prevent the recurrence of castration-resistant prostate cancer.
In this week's Cancer Matters podcast, Dr. Bill Nelson speaks with Dr. Venu Raman about his work to develop a cancer drug targeting a gene that stabilizes tumors.
Raman’s drug discovery began with research to understand the effect of secondhand smoke on breast cancer. It led him and his team to develop a first in-class drug called RK-33. Countless hours in the lab and hundreds of experiments and assays later, Raman and his team have developed and patented a small molecule inhibitor of the DDX3 gene, an exciting first-in-class pharmaceutical.