Moleculin Biotech, Inc. is a pre-clinical and clinical-stage pharmaceutical company focused on the development of game-changing anti-cancer drug candidates, many of which are based on discoveries made at M.D. Anderson Cancer Center. Each of our projects represents a breakthrough discovery and a highly disruptive technology.


Cell Signaling And Oncogenic Transcription Factors

Cellular biology depends upon signaling mechanisms to regulate functions such as cell growth, death and adaptation. Signal “transduction” is such a mechanism that converts an upstream stimulus to a cell into a specific cellular response. Signal transduction starts with a signal to a receptor or via a compound capable of passing through the cell membrane and ends with a change in cell function.  The end result of this signal is often the activation of “transcription”, whereby genetic information is expressed and, in the case of oncogenic transcription, disease processes are initiated or maintained.

Receptors span the cell membrane, with part of the receptor outside and part inside the cell.  See diagram below. When a chemical signal represented by a specific protein binds to the outer portion of the receptor, it conveys another signal inside the cell.  Often there is a cascade of signals within the cell, wherein an upstream inducer starts a chain of events that resembles a domino effect.  Collectively, this sequence is referred to as a “signaling pathway.” Eventually, the signal creates a change in the cell function by changing the expression of specific genes and production of specific proteins within the cell, and again, in the case of tumor development, such expression results in unwanted inflammatory and proliferative processes.

Importantly, while normal healthy cell function relies on signaling mechanisms, diseases are capable of co-opting these mechanisms with negative consequences.  Proliferative and inflammatory diseases depend upon signaling pathways that are responsible for coordinating functions such as cell growth, survival and cell differentiation.  A particular class of proteins referred to as Signal Transducers and Activators of Transcription (such proteins are “STATs”) plays an important role in regulating the process of disease cell survival and proliferation, angiogenesis[1] and immune system function and is persistently activated in a large number of human inflammatory processes and in hyper-proliferating diseases.  Because certain of these proteins are known to be co-opted by tumor cells, we refer to them as “oncogenic transcription factors,”  of which certain STATs are a subset.


Some STATs, such as STAT3, can be activated by any one of many different upstream inducers, making them very difficult to target by blocking just one or more of these upstream inducers. We believe that blocking a targeted STAT directly rather than via its multiple upstream inducers should result in greater efficacy with lower toxicity.

In the diagram shown here, any one of many different pathways (some of which are shown here as Growth Factor Receptors, Cytokine Receptors and Non-Receptor Tyrosine Kinases) triggers the activation of STAT3 proteins in a process called “phosphorylation”.  In this process, phosphates attach to corresponding receptors on STAT3 and the two phosphorylated STAT3 (“p-STAT3”) proteins bind together in a pair referred to as a “dimer”.  Once the dimer is formed, it enters the cell nucleus and triggers gene transcription.   Conversely, if we prevent the dimer from forming (i.e., by blocking phosphorylation), we can prevent the triggering of unwanted gene transcription and effectively inhibit the disease process.

The upstream effectors shown in this diagram (SRC, JAK and ABL[2]) are just some of those capable of activating STAT3 once they themselves are activated by a variety of signal compounds.  The complexity and diversity of pathways capable of activating STAT3 makes it very difficult to develop safe and effective drugs that attempt to target the upstream effectors.


Published research has identified STAT3 as a master regulator of a wide range of tumors and clearly links STAT3 activation with the progression of these tumors.  For this reason, it is believed that inhibiting the activation of STAT3 should be an effective way to reduce or eliminate the progression of these diseases.

Many research efforts have been directed toward development of specific methods to control activation of STAT3, but most have focused on targeting the upstream effectors of these pathways like growth factors, cytokines, and specific kinases including Janus kinases (JAKs). However, we believe that the multifactorial nature of the activation of STAT3 limits the effectiveness of such upstream approaches. Since the activity of p-STAT3 is a final and determinative step in triggering unwanted transcription, we believe it is preferable to inhibit p-STAT3 more directly and independently from upstream effectors.


We believe the WP1066 Portfolio represents a novel class of agents capable of hitting multiple targets, including p-STAT3, regardless of their upstream method of activation. By inhibiting the presence of p-STAT3, WP1066 directly attacks tumor cells, as has been demonstrated in numerous preclinical tests involving a wide range of tumor cells. We believe the effectiveness of WP1066 is not only the result of attacking tumors directly, but also indirectly by stimulating the immune system, increasing the patient’s natural ability to fight off tumor development. STAT1 is believed to stimulate T-cell activity and thereby the immune system responsible for fighting tumors. WP1066 has been shown to increase the activity of STAT1 at the same time it inhibits the activity of p-STAT3. We believe this dual activity makes WP1066 a uniquely promising anticancer drug candidate.

We believe the combination of the direct and indirect effects of WP1066 are to be credited with significant tumor suppression and increased survival in a number of in vivo cancer models. Below is one example showing a dramatic increase in survival by treating mice with metastatic melanoma with WP1066.

In Vivo Activity

In experimental biology, in vitro  (Latin for “in glass”) studies are those that are conducted using components of an organism that have been isolated from their usual biological surroundings in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments are commonly called “test tube experiments”.  In contrast, studies that are conducted with living organisms in their normal intact state are referred to as in vivo (Latin for “within the living”). We have shown in vivo that WP1066 inhibits tumor growth and blocks angiogenesis.  As well, we have shown in numerous mouse tumor models that WP1066 dramatically increases survival.

In vivo activity has been confirmed in a wide range of tumors, including metastatic melanoma, glioblastoma, head and neck tumors, bladder cancer, renal cancer and pancreatic cancer.

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