Precision medicines have dramatically altered the cancer treatment landscape and resulted in therapies that are targeted to the right patient populations where they can have life-changing benefits. Yet, the strength of many of these small molecule precision medicines is also a weakness because they rely on targeting oncogenic driver proteins, and in response to therapeutically targeting these proteins, tumors become drug resistant in a large percentage of patients.

Halda is pioneering the development of RIPTACTM therapeutics, which stands for Regulated Induced Proximity TArgeting Chimeras. A key differentiator of RIPTAC therapeutics is that they do not rely on oncogenic driver proteins because they use a novel heterobifunctional mechanism that selectively targets cancer cells in a different way and induces a cell-killing effect on the cancer cell. This selectivity opens up a whole new realm of targets that are non-oncogenic cancer-specific proteins, along with the powerful potential to overcome the challenge of drug resistance and bring a new class of precision medicines to patients.

The evolutionary path to RIPTAC therapeutics
by Prof. Craig Crews

The RIPTAC drug modality is an evolution of my Yale lab’s multi-decade work in heterobifunctional small molecule drugs. Our lab widely embraced the concept of heterobifunctional small molecules, which are drugs composed of two different ligands that bind to two different proteins. With targeting chimera (TAC) technology, these molecules are able to hold the two proteins together, so they interact to induce novel pharmacology. A whole new field of therapeutics have now evolved under the umbrella of “induced proximity” which allow drug hunters to use this approach to impart novel biology to tackle human disease.

The outcome of our first ‘light bulb moments’ with heterobifunctional drugs was my lab’s 2001 paper on PROTAC® (PROteolysis Targeted Chimeras) degraders. We built unique expertise in the development of PROTAC degraders as the first heterobifunctional drugs both in my lab and at Arvinas, the biotech company I founded in 2013 to commercialize PROTAC degraders. I started Halda to pursue new directions with the RIPTAC class of molecules. The truly innovative mindset we took with RIPTAC therapeutics was to envision a cancer-targeting mechanism that does not rely on oncogenic driver proteins.

The two components of a RIPTAC molecule are a ligand to a differentially expressed protein in tumor cells (targeting protein) and a ligand to a protein with an essential function (essential protein). The RIPTAC molecule holds these two proteins together in a stable trimeric complex which involves the formation of neo protein-protein interactions, which leads to abrogation of the essential protein function. This “hold and kill” mechanism results in selective cancer cell death.

RIPTAC therapeutics combine the power of several drug modalities. Like antibody-drug conjugates (ADCs), bispecific T cell engagers (BITEs), CAR-T cell therapies and radioisotopes, RIPTAC therapeutics do not depend on oncogenic drivers and have killing mechanisms that work across many mechanisms of drug resistance. However, they have the advantages of small molecules in that they can target intracellular proteins and are simpler to manufacture and deliver. We see broad potential for RIPTAC therapeutics to offer oral, selective, widely applicable cancer cell killing mechanisms that can be used in advanced cancer patients where resistance has emerged, as well as in earlier stage cancers. We see exciting possibilities ahead.

Bringing RIPTAC therapeutics from concept to reality
by Dr. Kat Kayser-Bricker

I joined Halda shortly after it was founded, following a decade in R&D leadership at Forma Therapeutics where I initially found my fit in early stage biotech. I enjoyed the all-hands-on-deck culture and fast pace as one of the first Forma employees, and I was ready to start a new venture. In particular, I completed my PhD and postgrad work in chemistry labs at Yale University and was excited about the prospect of joining a company out of the Yale community. During my graduate training, I was a neighbor to the Crews lab and had a front seat to the exciting work on PROTAC degraders that was emerging in the early 2000s. When I heard through my network that Professor Crews was founding another new biotech company, I was thrilled at the opportunity to invent the next generation of ‘TAC’ technology with a world leader in the space.

We set out to evolve RIPTAC therapeutics across two trajectories – scientific and business – to enable Halda to thrive as a biotech company.

Since RIPTAC therapeutics were an entirely new drug modality, we had challenging and interesting scientific work ahead of us. We needed to establish the foundational platform and provide evidence for the underlying mechanism that we envisioned. In order to do this, our team needed to develop chemical biology systems to build and test these new molecules. We needed to interrogate the new “rules of the game” and demonstrate our “hold and kill” mechanism. In the meantime, we faced another challenge: a lack of adequate physical space. We were a team of 10 working in two offices, along with an antiquated lab room from the 1980s era. During a booming time for biotech, there was a shortage of lab space everywhere, including New Haven. In true biotech fashion, we were scrappy, rolled up our sleeves and made it work!

Our scientific work ramped up, and we developed methodical ways to build RIPTAC molecules. We created a powerful chemical biology model that allowed us to interrogate each step of the novel mechanism of action to show the ability to selectively kill cancer cells. Ultimately, we compiled and published our work showing the proof-of-concept studies of the RIPTAC mechanism in January 2023, described here. We are excited by the potential of the RIPTAC mechanism to provide novel oncology therapies to address limitations of today’s existing precision medicines.

During these months when we were realizing the promise of RIPTAC therapeutics in our scientific work, the world around us was in lockdown as the COVID pandemic emerged. Like other biotech companies, we had established procedures so that our scientists could continue to do experiments safely at work. On the business side, it was time to develop a shortlist of the first cancer applications we could pursue for these therapeutics to make a meaningful impact to address unmet needs. During the social distancing required in a pre-vaccine COVID world, our team met fireside on the outdoor patio of Professor Crews’ house for a brainstorming session. We were wrapped in fleece blankets in winter as we discussed the promise of dozens of potential RIPTAC opportunities across many cancers.

The possibilities were, and continue to be, wide-ranging: the “menu” for designing RIPTAC therapeutics includes hundreds of cancer-selective intracellular protein markers as tumor-selective targeting proteins and hundreds of proteins with essential cell function. These opportunities presented our small molecule scientists with the new challenge of optimizing not only the interaction of a ligand with a single protein, but to maximize it for two proteins, as well as a new protein-protein interface of a ternary complex, culminating with abrogation of the essential protein function and cancer cell death.

From a big picture perspective, it is exciting and liberating to be able to pursue entirely new types of targets beyond the well‑trodden path of cancer targets that are oncogenic driver proteins while optimizing these molecules to have limited effect on normal cells. Now that we have our first RIPTAC drug programs well defined and on the path to the clinic, Halda is stepping into the spotlight to advance RIPTAC therapeutics as the new cancer-fighting drug modality.

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