A New Era of Possibility: Addressing Coveted Undrugged Targets
We’re in an inspiring era of drug discovery. Our understanding of biological mechanisms and disease pathology has expanded, and we have new tools and techniques that magnify insights needed to develop optimized medicines. As a life-long drug hunter that has always harnessed my interest in human biology to make better medicines, I’m energized by the immense potential of new therapeutic modalities being explored by the biotechnology community. These new platforms can expand the possibilities of being able to drug the broader universe of disease-causing targets and pathways that industry veterans have been attempting to solve for decades. Even before I went to university, I knew I wanted to be a part of creating solutions to tackle diseases by going after novel targets with strong biological rationales. I’ve had the honor of being a part of bold teams seizing this moment in time, leveraging new knowledge and technologies, and pushing the boundaries of what’s possible in this quest.
Selecting the right drug targets is crucial to the drug discovery funnel and significantly influences a company’s success both presently and in the future. I have spent much of my career advancing small molecule medicines across an expansive list of known disease-causing proteins. In my previous roles, focusing on traditional small molecule inhibitors was a comprehensive multi-step cascade due to the inherent mechanism of the molecules. In some cases, the functional site was obvious, in others, including many transcription factors, extensive efforts needed to be undertaken to understand the functional sites and where we wanted our drugs to bind. There are many transcription factors which are highly desirable drug targets – particularly those that are lineage specific and those which are activated only in a state of disease by specific stimuli. Therefore, I spent years with teams working to apply the technology of the time to challenging intractable targets, many of them being elusive transcription factors.
I remember first learning about targeted protein degradation (TPD) close to a decade ago when I was working in a large pharmaceutical company. I was impressed by the elegance of the biology and its promise to expand therapeutic possibilities in a disease-agnostic manner by tapping into a key cellular system through proximity-based interactions. Here was a technology, where in principle you can bind anywhere on the protein, where you didn’t have to understand the functional site, deal with homology of functional sites between proteins (i.e., selectivity issues), or worry if blocking one functional site was actually enough to stop all the protein’s activities. I was thrilled when the opportunity arose to lead research efforts and oversee unique strategies at Kymera, an early pioneer in the TPD field. In this environment, I could go all-in and use this technology to address the undrugged and inadequately drugged proteins, such as transcription factors and scaffolding kinases, involved in so many debilitating diseases. Additionally, all the targets in Kymera’s portfolio are further derisked with clear validation through human genetics/causal biology and clinical validation.
With this approach, coupled with our team’s deep chemistry, biology, and drug development expertise, we are advancing a pipeline of highly potent, selective, oral small molecule degrader programs targeting these highly credentialed, disease-causing proteins in areas of significant patient need. This sustainable and scalable research engine has positioned us to address targets in key immuno-inflammatory signaling pathways. Our first success here was with KT-474, our oral IRAK4 (scaffolding protein) program. After seeing early clinical data from KT-474, the first degrader program to enter clinical development in immunology, which demonstrated a strong alignment between our preclinical profile and clinical results, we were confident that our team and approach were well-equipped to tackle a broad range of historically undrugged but high value immunology targets.
Learn more about Kymera’s toolbox of integrated approaches to drug discovery and development
That brings us to KT-621, our investigational, once daily, oral STAT6 degrader. STAT6 has been a long-sought-after transcription factor for decades by the biopharma industry given its role in several allergic and atopic diseases. We knew we had the toolkit to take on the challenge. Fast forward, in preclinical studies, KT-621 demonstrated picomolar potency with refined drug-like properties (orally bioavailable with systemic distribution to all target tissues). Additionally, preclinically KT-621 has shown in vitro and in vivo efficacy similar or superior to dupilumab, a blockbuster approved injectable biologic in the same pathway, highlighting the promise of TPD. Here we have an oral pill compared to injectable IL-4 biologics with the potential to reach a greater population in need.
Importantly, we won’t stop here. Our goal remains to expand our portfolio of oral medicines with biologics-like activity and deliver at least one IND per year. We are working diligently to deliver many more exciting new developments, which we hope to disclose at a consistent pace. In fact, this May we are excited to unveil our next oral immunology program. This is a genetically validated and long sought after target, a previously undrugged transcription factor that has the potential to be a first-in-class agent for multiple rheumatic and autoimmune diseases where there are few and ineffective options for patients.
As the Head of Research, I’m humbled to be a leader at a company dedicated to driving real, near- and long-term change. Our team’s commitment to innovation and first-in-class science will position us well on our mission to build a global medicines company that revolutionizes the treatment of immunological diseases. While we’ve had many great accomplishments, we believe the best is still ahead as we work to tackle complex scientific challenges/targets and create unprecedented possibilities for patients.
Join our pioneering team at the forefront of change – apply today!
Juliet
Juliet Williams, PhD
Head of Research
Kymera Therapeutics