Boston, Mass., Nov. 9, 2021 — HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of first-in-class allosteric therapies targeting regulatory sites on proteins referred to as “natural hotspots,” today announced new data validating its Smart Allostery™ platform in the elucidation and preclinical evaluation of a novel allosteric inhibitor of the E3 ubiquitin ligase CBL-B. The data will be presented at the Society for Immunotherapy of Cancer (SITC) 36th Annual Meeting, which is being held from November 10-14, 2021.
“CBL-B’s role as a master negative regulator of T cells and NK cells makes it a very attractive target for cancer immunotherapy, but it has proven difficult to inhibit with traditional small molecules,” said Geraldine Harriman, Ph.D., Co-Founder and Chief Scientific Officer at HotSpot Therapeutics. “We’re thrilled to share these new data showing that we can successfully inhibit CBL-B with a novel allosteric inhibitor identified through our Smart Allostery™ platform and promote T cell responses in vitro and in mice. To better treat patients, we need new mechanisms to enhance and sustain effective anti-tumor immunity and to address suboptimal responses. Our small molecule allosteric inhibitor of CBL-B may bring such benefit with the added advantage of convenient oral delivery.”
CBL-B sits at a pivotal node in immune cell activation, and its inhibition holds the potential to address several key mechanisms where translational data supports a causative role in suboptimal response to current immunotherapies. Because inhibition of CBL-B lowers the threshold for T cell and NK cell activation, even in the absence of co-stimulatory signals, it may bring benefit to patients with low antigen levels (e.g., low TMB), low inflammation (e.g., low PDL-1) and/or sub-par co-stimulation (e.g., low CD28).
HotSpot’s Smart Allostery™ approach offers a diversity of advantages in delivering highly selective and differentiated orally bioavailable medicines against proteins that are undruggable or poorly druggable targets, including CBL-B. The platform utilizes a suite of computational algorithms powered by machine learning to uncover natural hotspots that control protein function, employs an array of specialized assays to identify hotspot binders and subsequently uses chemistry to selectively drug these sites with allosteric inhibitors.
SITC Presentation Overview:
Title: Identification of A Novel Allosteric Oral CBL-B Inhibitor that Augmented T Cell Response and Enhanced NK Cell Killing in vitro and in vivo
Authors: Jun Kuai, Yingzhi Bi, Yilin Qi, Deborah G Conrady, Rajiv G Govindaraj, Graham Hone, R. Aldrin Denny, Ken Carson, Geraldine Harriman, Fang Wang
Poster Number: 864
Session: Novel Single-Agent Immunotherapies
Summary of Poster
- CBL-B is activated by tyrosine kinases and undergoes a large conformational change from closed inactive form to open active form.
- Through the utilization of HotSpot’s proprietary Smart Allostery™ platform, including its AI-powered SpotFinder™ technology, a druggable phosphoregulatory pocket was identified in the inactive form of CBL-B.
- HotSpot identified an inhibitor that binds to a regulatory hotspot on CBL-B, locking it in its inactive form, as confirmed by co-crystal structures.
- This molecule prevents CBL-B phosphorylation, inhibits E3 ligase activity, promotes cytokine release, enhances T cell proliferation, and stimulates NK cell activation/killing.
- In vivo, the molecule enhances T cells responses in anti-CD3 treated mice.
About HotSpot Therapeutics
HotSpot Therapeutics is targeting nature’s regulatory mechanisms to create allosteric medicines that are highly potent and selective and enable proteins to be drugged for the ﬁrst time. The company leverages its proprietary Smart Allostery™ technology, the ﬁrst and only platform designed to uncover, capture, and drug natural hotspots, a unique family of pockets involved in endogenous signaling that are critical to protein function in cells. Using bespoke chemistry and a powerful pharmacology tool kit, HotSpot is developing apipeline of ﬁrst-in-class small molecules for the treatment of cancer and autoimmune diseases. The company has successfully exploited natural hotspots across multiple target classes including E3 ligases, kinases, and transcription factors. To learn more, visit www.hotspotthera.com.