HotSpot Therapeutics recently announced FDA clearance of our Investigational New Drug (IND) application for HST-1011, our small molecule allosteric inhibitor of casitas B-lineage lymphoma-B (CBL-B). While the event is a big milestone for us as a company, as it represents our first IND filing, we hope the real significance of this breakthrough will be its contribution to the field of immuno-oncology (I-O).

We believe HST-1011 is differentiated, both in terms of how it functions and – importantly – how we’ve developed this selective molecule by deploying our Smart Allostery™ platform, which uses proprietary computer algorithms to identify functional pockets on proteins. We believe our approach offers a diversity of advantages for developing novel and differentiated orally bioavailable medicines.

Building a More Aggressive Immune Response

In scientific terms, HST-1011 is an orally bioavailable, selective, small molecule allosteric inhibitor of CBL-B, an E3 ubiquitin protein ligase critically involved in immune cell response. What that means is that HST-1011 is able to bind to and inhibit a natural hotspot on CBL-B, which is a master regulator of immune cell function, yielding the activation and propagation of a targeted anti-tumor immune response. By inhibiting CBL-B in this manner, it is easier for effector immune cells to be activated and to be less susceptible to being suppressed in the tumor microenvironment. That targeted function is what we believe will be the key to addressing the central limitation of existing I-O therapies: treating tumors that do not respond to immunotherapy and those that respond initially but eventually bounce back.

We’ve recently presented research that illustrates how this process works. The research shows how, in the mixed lymphocyte reaction (MLR) assay, which is a strong predictive correlate of the clinical activity of I-O therapies, the HotSpot CBL-B inhibitor demonstrated robust effects on cytokine release and T cell proliferation as monotherapy. Additionally, CBL-B inhibition demonstrated synergistic activity in the MLR assay when combined with existing checkpoint inhibitor-type anti-PD1 therapies. The result has been a more aggressive immune response in vitro and in vivo, and we are excited about the potential for our approach as we embark on the clinical trial phase of this journey.

Allosteric Drug Development Goes Mainstream

The other big breakthrough behind this milestone is the differentiated process we’ve used to develop HST-1011. The therapy was discovered using our proprietary Smart Allostery™ platform which uses computer algorithms to identify functional pockets on proteins that control their function. These functional pockets, which we refer to as “natural hotspots,” serve as molecular on/off switches and can be used to transform protein activity with innate selectivity. To date, we’ve been able to identify 1,500 proteins containing natural hotspots that control protein function outside of traditional active site cellular function.

From there, it becomes possible to understand how specific pockets drive the behaviors of the protein and thereby design pharmacological modulators that impact cellular function beyond the limitations of existing active site small molecule approaches to drug development.

Ultimately, what this first IND for HotSpot Therapeutics represents is not just one exciting potential new therapy, but the recognition of a breakout approach to clinical discovery that taps the power of machine learning along with innovative biology, chemistry and biophysics to unlock new frontiers.  

We believe those attributes are key to a more targeted, durable immune response that has the potential to usher in the next wave of immuno-oncology innovation. Together, as we initiate our Phase 1/2 study of HST-1011 in the first quarter of this year, we look forward to continuing to break down barriers in I-O innovation for this therapy and the others we expect to follow its lead.