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Therabene – Developing A New Class of Molecules Called Degraders to Attack Key Target Proteins Involved in The Proliferation of Cancer Cells

Mario DiPaola PhD/MBA

Founder/ CEO



Mario DiPaola


Interview conducted by:

Lynn Fosse, Senior Editor

CEOCFO Magazine

Published – July 17, 2023

CEOCFO: Dr. DiPaola, what is the idea behind Therabene?

Dr. DiPaola: Therabene's founding was slightly over three years ago; the Company’s mission has been to develop a new class of molecules called degraders, also known as PROTACs. These are complex heterobifunctional molecules that have been demonstrated to target and successfully degrade proteins of interest. In our case, we want to develop degraders that would allow us to attack key target proteins involved in the proliferation of cancer cells. By attacking and degrading such oncogenic proteins, we hope to stop cancer growth and offer cancer patients the prospect of a longer life.  

CEOCFO: What is the definition of degrading a molecule?

Dr. DiPaola: What that means is that the protein of interest, through the use of a specific degrader, is enzymatically tagged with a small tag called ubiquitin. Once the protein is tagged with several ubiquitin molecules, the ubiquinated protein is then directed to the proteasome, where it is proteolyzed and, thus, eliminated.

CEOCFO: Why this approach and why now?

Dr. DiPaola: This approach was developed in academia, and it is an approach that has been worked on for well over a decade. More recently, this technology has gained the interest of many companies in the pharmaceutical and biotechnology industries. While inhibitors of oncogenic proteins have had some degree of success in a number of cancers, PROTACs can actually target pathogenic proteins, leading to improved regulation of the related signaling pathway. Such regulation cannot be achieved by conventional therapy using inhibitors. Furthermore, the use of PROTAcs in cancer is less likely to lead to drug resistance and cancer recurrence as seen with the use of kinase inhibitors.

CEOCFO: You have a long history and medical background; why do you think this could work?

Dr. DiPaola: It is a novel modality with strong promise. It is an approach that will not work for every type of cancer. This modality will work well for those cancers for which there is a well-defined pathway with key protein drivers, such as kinases and other cell cycling regulating proteins or transcription factors that lead to oncogenesis. Attacking and degrading these key oncogenic drivers should result in successful control and possibly outright destruction of the cancer. Will the use of PROTACs result in an actual cure for cancer? Most likely not, but as with all oncology therapies, the game plan is to manage the disease for as long as possible, while affording the patient a good quality of life.

CEOCFO: Your site shows pancreatic cancer and triple-negative breast cancer as targets. Why?

Dr. DiPaola: Triple negative breast cancer currently does not have any good treatments. While there have been some reasonably effective therapeutics introduced for breast cancer, triple-negative breast cancer remains an unmet medical need. Use of a degrader as a stand-alone therapy or in combination with other drugs should provide an effective tool for patients afflicted by this type of cancer. Similarly, pancreatic cancer remains one of the deadliest types of cancer with a 5-year survival rate of less than 10%. Based on some early work in our labs and elsewhere, we believe that targeted PROTACs promise to potentially be an effective approach for fighting pancreatic cancer.

CEOCFO: What are you working on today?

Dr. DiPaola: We are currently working on optimizing our lead product against target triple-negative breast cancer. To-date, Therabene has done several in vivo studies in mice and seen consistent tumor reduction responses. We plan to continue to develop this lead product and bring it to IND (Investigational New Drug) stage within a year.

We have also developed several degraders that are quite effective against pancreatic cancer cell lines, based on in-vitro data. We are continuing to optimize the chemistry of these new constructs and we expect to take these into in-vivo model studies in the next six months.

CEOCFO: Where are the investment and medical communites; do people understand what you are trying to do at Therabene and are they onboard?

Dr. DiPaola: Right now, there is quite a bit of interest in this new platform and has gained more visibility over time. Nonetheless, there is also a lot of educating that needs to be done, especially within the investing community, on how these molecules work and how potentially they could help cancer patients. While there is some enthusiasm, there is also quite a bit of misgiving about this novel technology, consequently it is an uphill battle trying to convince investors that this is a worthwhile new approach and that it merits investments to propel its development.

Of course, I am a strong believer in this new platform, and I am committed to doing all that it takes from both the scientific as well as the investment sides to see this platform succeed.

CEOCFO: What have you learned about getting through to investors?

Dr. DiPaola: This is probably not the best of times to attract investments; it takes tenacity and patience, and we need to keep on knocking on doors until we find the right people who are willing to listen and invest. There is no quick solution, it takes time, patience, and tenacity.

CEOCFO: Are there many other organizations trying to do work in this arena; what is the competitive landscape?

Dr. DiPaola: A number of organizations have been founded around this new technology and they were successful in attracting large investments, at least a few years ago when the investing landscape was much more favorable. Some of these early entry organizations have since done IPOs and are currently publicly traded companies.

There are also many new entrants into this degrader technology space that have been founded in the past 2-3 years, developing novel degrading constructs.  So, while the field is not terribly crowded, yet; a few notable successes by some of these early degrader companies will likely and dramatically change the environment.

CEOCFO: What if anything has surprised you in what you have learned so far?

Dr. DiPaola: The surprise has been the scarcity of investments available either through VCs or Pharma. Some of this is a consequence of VCs pulling back quite strongly in the past two years from investing in biotechnology. From our end, we have been able to raise some funds but primarily through private and small angel investors. I certainly hope that this current sentiment by VCs to wait until there is significant validation of experimental drugs/platforms through either an IND filing or availability of phase I (or even phase II) data changes so that early-stage life science discoveries can be properly funded.

CEOCFO: What surprised you about the science?

Dr. DiPaola: The chemistry required for the preparation of these degraders is quite complex. Not only are there two functional sides of the molecule and the moiety binding to the protein of interest must be of high affinity to minimize off-target binding and, thus, toxicity, but then there is a linker that links the degrader two functional moieties. The linker can play a significant role in stabilizing the degrader entity, as well as effecting the solubility, bioavailability and clearance of the degrader.

We have had many unpleasant surprises and some real challenges. Our approach, typically, is to initially conduct quite a bit of “in silico” computational analysis of any new construct to ensure specificity of the degrader and then subject the degrader to ADME modelling software. Once we see acceptable predictive data, then we launch into the synthesis of the degrader. In spite of all the de-risking through in-silico simulations, after the synthesis of the degrader and acquiring the necessary in-vitro validation data, there is no guarantee that the degrader will necessarily perform well in-vivo.

CEOCFO: Why pay attention to Therabene?

Dr. DiPaola: The Therabene team has generated a series of very interesting and clinically promising molecules in the past couple of years. These molecules have already been tested in-vitro and some have gone into in-vivo studies. We have seen very promising efficacy data, so far, with minimal toxicity; therefore, we are very enthusiastic in pushing forward with the development of these molecules.

As I mentioned before, we rely quite a bit on artificial intelligence and in-silico modeling to de-risk the development of our degrader molecules. Also, in the past two years, we have built a good network of service providers/partners for both synthetic chemistry and in-silico work to augment our internal expertise. By utilizing our internal know-how and leveraging our external network of labs, we can move our assets through the development cycle quite rapidly.

While we do need additional investments to further move along some of the lead products that we have in our pipeline, we have established solid foundations with our lead product and hope to file an IND by mid to late 2024.

Therabene | Mario DiPaola PhD/MBA | Protein Degraders Cancer | Breast Cancer Degraders | Therabene – Developing A New Class of Molecules Called Degraders to Attack Key Target Proteins Involved in The Proliferation of Cancer Cells | CEO Interviews | Medical Companies | Protac | Degrader | Oncogenic | kinase inhibitor | triple negative breast cancer | ADME | In-silico | Therabene Press Releases, News, Linkedin

“By attacking and degrading such oncogenic proteins, we hope to stop cancer growth and offer cancer patients the prospect of a longer life.”
Mario DiPaola PhD/MBA






“We have established solid foundations with our lead product and hope to file an IND by mid to late 2024.”
Mario DiPaola PhD/MBA