HPK1 has long been of interest as a potential pharmacological target for immune therapy because of its central role in negatively regulating T cell function. The development of a small molecule HPK1 inhibitor remains challenging because of the need for high specificity relative to other kinases that are required for efficient immune cell activation. We will present our efforts at generating selective HPK1 inhibitors to enhance the anti-tumor immune response.

HPK1 negatively regulates T & B cell signaling. Our initial HPK1 inhibitor demonstrated a modest TPP. Dissatisfied, we renewed our efforts with new chemotype designs & refined animal models. Our second-generation candidate showed excellent in vitro, immunological & safety profiles. We observed good in vivo efficacy, both as a single agent and with immune checkpoint inhibitors. GRC54276 is progressing through a multi-center, Phase I clinical trial in patients with solid tumors.

High levels of Regulatory T cells (Treg) accumulation in the tumor micro-environment (TME) have been shown to dampen the antitumor immune response and lead to poor prognosis in patients with various types of cancers. Treg are recruited to the TME through selective interactions of the chemokine receptor CCR4 and chemokines CCL17 and CCL22. The discovery and early clinical development of FLX475, a potent and selective CCR4 antagonist will be described.

UBE2N is a novel therapeutic target that controls convergent signaling node implicated in cancer immune signaling. We have successfully used Micro-Tag cell target engagement technology for discovery of novel UBE2N inhibitors. Preclinical assessment of cellular target engagement is essential for development of safer and more effective therapeutics. Infusion of such critical data into drug discovery significantly accelerates drug discovery, reduces failure rate of drug candidates and improves clinical translatability.

The av integrins (avb1, avb3, avb5, avb6, avb8) are a subset of a family of heterodimeric transmembrane proteins that mediate cell-cell and cell-extracellular matrix signaling. I will discuss the role of integrins in immuno-oncology and will describe the development of our integrin inhibitor library. I will also present the challenges in targeting integrins with small molecule drugs.

BioAge is analyzing proprietary human-omics and longitudinal health outcome data to identify novel neurodegeneration drug targets. Our analyses showed that NLRP3 levels rise with age and correlate positively with mortality and cognitive decline. We have synthesized new compounds that inhibit NLRP3 inflammasome in vitro and in vivo, are as or more potent than known NLRP3 inhibitors, have novel structures and chemical properties, and penetrate the blood-brain barrier.

SHP1 is among the undruggable protein tyrosine phosphatase (PTP) superfamily and negatively regulates the immune responses in T cells and macrophages. Studies revealed that SHP1 deletion in immune cells or whole-body delays tumor progression. From high-throughput screening, we have developed the first-in-class covalent inhibitor that target SHP1 with unprecedented selectivity. The inhibitor is orally bioavailable and inhibits tumor progression via activation of T cells and macrophage activity.

Modulating target proteins via the ubiquitin-proteasome system has recently broadened the scope of pharmacological inventions. Stimulator of interferon genes (STING) activation is a promising strategy for immuno-oncology via promoting systemic antitumor immunity. However, from the current clinical investigations of STING agonists, dysregulated STING expression or poor STING agonist pharmacokinetics pose major challenges that limit the robust antitumor response. Herein, we propose UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to overcome these limitations.

IKZF2 (Helios) is a member of the Ikaros family of zinc finger transcription factors. IKZF2 genetic knockout in mice was shown to destabilize immune-repressive regulatory T cells (Tregs) and it was hypothesized that selective IKZF2 downregulation might safely enhance immune responses to tumors. Here, we present the development of NVP-DKY709, a reprogrammed IMiD-derived molecule that selectivity degrades IKZF2/4 but not IKZF1/3. Non-human primates treated with DKY709 display rapid and sustained degradation of IKZF2 in peripheral blood cells and enhanced response to immunization. DKY709 is a first-in-class selective IKZF2/4 degrader being investigated in human clinical trials as an immunomodulatory drug.

I describe preclinical and clinical data for NX2127, a degrader of Bruton Tyrosine Kinase (BTK), a master regulator of B cells and implicated in cancer. We developed two unique and functionally distinct BTK degraders that harness cereblon (CRBN), an E3 ligase active in hematopoietic cells. I describe the BTK degrader that also has the ability to induce degradation of neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3).

E1A binding protein (p300) and its paralog CREB binding protein (CBP or CREBBP) are key transcriptional co-activators that play a critical role in gene expression in both tumor and immune cells. Our efforts in understanding the distinct advantages of inhibition vs degradation of CBP/p300 for use in cancer therapy resulting from a combination of synthetic lethality, inhibition of pro-tumorigenic signaling and activation of anti-tumor immune response will be presented