Breaking cancer’s will to survive
The challenge of being first
By Michael Seringer
The search for a novel compound on which to design a first-in-class cancer therapy is a long, arduous process. Daohong Zhou evaluated hundreds of compounds synthesized by the team of Guangrong Zheng, PhD, a medicinal chemist who specializes in the design and synthesis of natural and synthetic compounds at the University of Florida. Zhou and his team were looking for a compound that degraded a cancer’s survival signal, termed BCL-xL, without being toxic to blood platelets.
Daohong Zhou, MD
Professor of Biochemistry and Structural Biology; Director of the Center for Innovative Drug Discovery; Associate Director of Drug Discovery for the Mays Cancer Center
Company: Dialectic Therapeutics (private)
Compound: Novel, small molecule — DT2216 (patented)
Indication: Cancer, relapsed and refractory malignancies
Stage: Completed FDA investigational new drug application studies; in Phase 1 clinical trials, Mays Cancer Center
Timing: Approximately five years
Funding: Approximately $24 million
Taking a first-in-class compound from the lab to the clinic in an academic setting requires a competitive mindset.
“We were the first to creatively use the proteolysis targeting chimera [PROTAC] technology to overcome the on-target and dose-limiting toxicity of BCL-xL inhibitors,” Zhou said. “We are targeting cancer cells by converting the inhibitors into BCL-xL PROTACs that target BCL-xL to an E3 ligase minimally expressed in platelets but highly expressed in tumors.”
Zhou’s goal of developing a first-in-class, cancer-fighting molecule was realized when DT2216 showed promise in vitro and in vivo in both human tumor xenograft models and patient-derived xenograft models. Zhou’s team targeted cancer’s will to survive with the launch of Dialectic Therapeutics and its first-in-class compound DT2216.
The key to developing a compound with a unique mechanism of action and delivery starts with innovative ideas, cutting-edge technologies and solid medicinal chemistry and research.
“It took a number of years of hard work as a team to advance DT2216 into the clinic,” Zhou said.
Zhou compares the development of a first-in-class drug to the process of making beautiful art. Both require absolute dedication, close attention to detail and constant assessment and iterative improvements.
In addition, like artists who become popular in their lifetime, the research teams benefit from a little luck, Zhou said. By assembling a team of company founders composed of a medicinal chemist, physician scientist and biologist — and supported by Texas biotechnology experts and Dialectic Therapeutics investors and board members David Genecov, MD, and John Harkey — Zhou’s team has helped create their own luck.
Developing a first-in-class compound
The problem with developing a first-in-class drug is there is no previous research to guide the process.
“There is no literature to refer to,” Zhou said. “That’s the challenge with developing a firstin-class drug; everything is new. Figuring out everything from the basic research to the proper dose regimen is difficult and time consuming when you have nothing to build on.”
Along with being a truly novel compound, DT2216 is too large to be absorbed from the GI tract and therefore requires intravenous therapy. Developing a lipid-based microemulsion to better deliver the drug to tumor cells provided additional intellectual property that enhanced the company’s overall product portfolio.
DT2216 is a first-generation compound built using a proprietary and novel antiapoptotic protein targeted degradation (APTaD™) technology platform. Taking a first-in-class compound from the lab to the clinic in an academic setting requires a competitive mindset, according to Zhou. Both the Food and Drug Administration’s investigational new drug application and human trials are an exhaustive process more aligned with the mindset prevalent in the pharmaceutical industry versus an academic institution, Zhou said.
Innovative ideas need to be not only fostered by the right team, but also financed by partners with experience in biotechnology investing and drug discovery.
Competing against the pharmaceutical industry in drug development is very difficult; however, bringing a first-in-class molecule to the clinic gives startup biotech firms a slight advantage because they can change directions faster. They also maintain control over their molecule through animal and human trials. This is advantageous because they understand their compound better than anyone else and can catch small problems in the toxicity testing or clinical trials that might not be caught by another team not as familiar with the biochemistry and biology of the compound.
Zhou believes much of the current success of Dialectic Therapeutics is the result of running a lean organization that invests everything back into research because it holds the vast majority of the equity.
“You need a strong team with basic researchers to conduct cutting-edge research, clinicians who know patients’ needs and how to translate basic research into the clinic, and a team who can help to advance leading compounds through the regulatory process into the clinic,” Zhou said.
Building the right focus and financing
Building an efficient drug development process requires team members to focus time and resources into research and development. The core value of scientific discovery comes at the expense of the usual biotech startup culture, which is focused on public perception, funding rounds and exit strategies. Getting a compound to the clinic is simply too difficult and expensive to focus on anything other than the drug. The motivating fact that many patients with incurable cancer are counting on a successfully designed drug increases the already high stakes.
“Drug discovery and development research is high risk and high reward,” Zhou said. “Because the ultimate goal of our research is to improve health and quality of life and save lives, it is very satisfying to see that our hard work may eventually benefit patients.”
Innovative ideas need to be not only fostered by the right team, but also financed by partners with experience in biotechnology investing and drug discovery. Attracting the right private equity partners depends on a “well-validated therapeutic target with a large enough market to motivate investors,” Zhou said. Too many researchers fail to assess market size and find out that there is little investor interest until it’s too late, once too much time and money have been invested in the wrong target.
“For investors to allocate resources to expensive preclinical and clinical studies, they have to see a large enough market for the compound,” Zhou said.
Just as important is selecting the right site on the target. For example, some PROTAC candidates never work because there is no adjacent lysine for the compound to act on. Then it is crucial that the compound be completely novel so that it can have strong intellectual property protection. It is almost impossible to attract investors to a compound that is already in the public domain, no matter how useful it is.
Taking advantage of research grants is beneficial to startup drug discovery firms because this provides the necessary funding without dilution of ownership and loss of control of the startup company. Zhou and his team were awarded key grants from the National Institutes of Health and The Cancer Prevention and Research Institute of Texas to help fund development of DT2216. These grants create value beyond the dollars provided by validating the science and reducing risk for future investors, providing needed momentum for getting the compound through human trials.
Zhou’s success provides a blueprint for how other universities can enhance their own drug development programs. Universities can create external review of the commercial possibilities of novel targets and compounds, they can train faculty to spin off their own companies, and they can connect those companies with private equity.