‘The more the merrier’ rarely applies in biology—life is maintained by a delicate balance of interactions among molecules, cells, tissues and organs. For instance, blood vessels are essential for delivering blood rich in oxygen and nutrients to all parts of the body. Angiogenesis—the sprouting of blood vessels—is important during growth, development and wound healing.
However, aberrant angiogenesis can also result in disease. For example, in the eye, the overgrowth of blood vessels can give rise to a condition known as wet age-related macular degeneration (AMD), whereby the vessels leak blood and fluid into the retina. Left untreated, the bleeding forms a scar and causes vision loss. Similarly, in cancer, solid tumors secrete factors that promote angiogenesis so that the tumor receives nourishment and can sustain its growth, while also gaining an ‘escape route’ to metastasize to other parts of the body.
An A*STAR spin-off company, SiNOPSEE Therapeutics, aims to tackle the problem of unwanted angiogenesis with its pipeline of small molecule drugs that block the downstream signaling from angiogenic factors. A*STAR Research spoke to Uttam Surana, one of SiNOPSEE Therapeutics’ four founding members and a Research Director at A*STAR’s Institute of Molecular and Cellular Biology (IMCB), about how he is taking his research from bench to bedside.
1. Why are you interested in molecular targets that regulate angiogenesis?
My research primarily focuses on networks that control the dynamics of cell division. Hence, anticancer therapeutics that can inhibit tumor cell division and trigger cell death have always been on my radar.
Angiogenesis is important in this context because blood vessels supply nutrients and oxygen to tumors, helping them grow, survive and invade other tissues. Furthermore, abnormal blood vessel formation is also involved in debilitating ocular diseases such as AMD, which can lead to complete blindness.
Thus, we had reasoned that by targeting angiogenesis, we would serve the therapeutic need simultaneously for two major disease domains: oncology and ophthalmology.
2. What are some of the molecular targets that SiNOPSEE Therapeutics is developing drugs against?
A major class of molecules we target are the receptor tyrosine kinases (RTKs), which regulate many signaling pathways involved in cell growth and division. Some of the targets in this group, like PDGFR, VEGFR and Flt3, are involved or implicated in tumor growth and angiogenesis.
Besides RTKs, our repertoire of molecular targets also includes regulators like cyclin-dependent kinases (CDK). CDK 8 and CDK19, for example, control transcription and are frequently deregulated in colon, prostate and breast cancer. As they are considered an important group of therapeutic targets, we intend to develop drugs against them.
3. Could you describe the process of drug discovery and development at SiNOPSEE Therapeutics?
We first use ‘humanized’ yeast strains (developed with the help of a Singapore Therapeutics Development Review grant from A*STAR) to identify inhibitors against various disease targets, such as RTKs or metabolic enzymes, before testing them on human cells. By humanized, I mean yeast strains that have human proteins or pathways integrated into the yeast genome through genetic engineering.
Essentially, we took humanized Baker’s yeast (Saccharomyces cerevisiae) and used them as a platform for designing drug screening strategies that can rapidly identify inhibitors against disease-causing proteins or pathways. These experiments eventually evolved into a collaborative project with the company MSD, where we sought to identify inhibitors against metabolic enzymes that are implicated in lung cancer.
During this process, my long-time collaborator Hong Hwa Lim and I developed a close collaboration with Chandra Verma and Srinivasaraghavan Kannan at A*STAR's Bioinformatics Institute (BII). We employed computational methods for improving the efficacy and selectivity of our system, and the four of us eventually became the co-founders of SiNOPSEE Therapeutics.
Finally, to build our chemical compound library, we received generous support from Kong Peng Lam, Executive Director of A*STAR’s Bioprocessing Technology Institute (BTI), and Wanjin Hong, Executive Director of IMCB. Our computational efforts were supported by Frank Eisenhaber, Executive Director of BII. These events ultimately helped to establish the current drug pipeline we now have.
4. How might small molecule inhibitor drugs be superior to other drug types in the context of oncology and/or ophthalmology?
For wet-AMD, as an example, the current standard of care for the condition involves injecting antibodies into the eye every few months. Even then, 30 to 40 percent of the patients do not respond well to this form of treatment.
Unlike antibodies, our most advanced lead candidate does not bind to the ligand that promotes angiogenic growth as antibodies do. Instead, the candidate is a small molecule that inhibits three RTK receptors (PDGFRα, PDGFRβ and VEGFR2) responsible for the abnormal growth of blood vessels. This difference in mechanism of action allows us to administer the drug as an eye drop, which is not possible with current antibody-based therapies.
5. What were some of the hurdles you and your team faced while founding SiNOPSEE Therapeutics?
Once we had identified, optimized and tested the first set of inhibitors against our targets, we decided to develop them as well-optimized, preclinical development candidates for wet-AMD. At that time, A*STAR's Experimental Therapeutics Centre (ETC) did not yet have measures in place to develop such therapeutics. Our other option, then, was to start a spin-off company and attract funding from angel investors to develop these lead molecules. So the four of us took the plunge and registered SiNOPSEE Therapeutics in December 2017.
Having no prior experience in running a start-up, a major hurdle was familiarizing ourselves with various administrative processes, like business registration, share distribution, licensing agreements and patents. We had to slowly learn the ropes while running our respective labs. We also assembled a Scientific Advisory Board with three eminent members to guide SiNOPSEE Therapeutics through its developmental path: Alex Matter, a drug discovery and development expert; Sir Tom Blundell, a renowned structural biologist; and Dorairajan Balasubramanian, an eminent scientist and the Director of the L. V. Prasad Eye Institute, India.
The greatest challenge, however, was finding investors who would provide funding to sustain our research. In this regard, we received some help and guidance initially from A*ccelerate, the commercialization arm of A*STAR, and subsequently from our personal contacts. A*STAR is a stakeholder in SiNOPSEE Therapeutics and has helped to connect us with various investors.
6. What is the current status of SiNOPSEE’s lead drug candidates and what are the company’s future plans?
SINOPSEE Therapeutics has now advanced the development of the drug molecules it licensed out from A*STAR. New chemical modifications have been introduced to increase the efficacy and selectivity of these compounds, and a new intellectual property filing has been made that is wholly owned by our company.
Meanwhile, our lead candidate against wet-AMD has been tested in both mouse and rat models. We have also ‘tuned’ its structure such that its pharmacokinetic parameters, such as ocular toxicity, are within a characteristic range for a good drug candidate, without compromising on drug efficacy.
Most notably, we have developed a proprietary eye-drop formulation for the efficient administration of our lead candidate. Given that the current standard-of-care for wet-AMD is the bimonthly eye-injection of an antibody marketed by Bayer, Novartis and Genentech, a therapeutic eye drop could be a game changer in the wet-AMD therapeutics domain.
We are now planning to test the lead candidate, in combination with our eye-drop formulation, in a monkey model, followed by a Phase 0, first-in-human trial. In addition to the wet-AMD project, we are looking to further develop our anticancer therapeutics and will be raising series A funding in the near future.