Hematopoetic progenitor kinase 1 (HPK1), a negative regulator of TCR signaling, is an attractive target for cancer immunotherapy. Although the role of HPK1 kinase domain (KD) has been elucidated, the function of its citron homology domain (CHD) remains elusive. Through a combination of structural, biochemical, and mechanistic studies, we characterized the structure-function of CHD in relationship to KD and demonstrated a central role for CHD in the regulation of HPK1 function.

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor overexpressed in various malignancies. DDR1 is activated upon binding to collagen in the extracellular matrix, and plays a role in tumor promotion, immune exclusion, and therapeutic resistance. A detailed characterisation of AUR109, a potent inhibitor of DDR1, in generation of profound anti-tumor immunity either as a single agent or in combination with immune checkpoint inhibitors will be discussed.

K-RAS oncogene is the most undruggable target in cancer. Mutated K-RAS is responsible for colon, lung, and pancreatic cancers. Targeting membrane proteins and cell surface receptors for degradation can open new applications for PROTAC drugs. Progenra has utilized a novel membrane associated ubiquitin ligase that preferentially degrades K-RAS and RTK receptors/membrane proteins. Given the DMPK and target engagement challenges of PROTACs we have also explored the discovery of molecular glues for selective degradations of K-RAS proteins. Comparative data for PROTAC and molecular glue for target degradation will be presented.

Galectins are a family of ß-galactoside-binding lectins that control numerous cellular processes in disease, including fibrosis, carcinogenesis, and tumour immune evasion. Evidence is emerging that blockade of more than one galectin may provide additional benefit within the oncology arena due to overlapping and distinct biological functions. This talk will focus on the validation and characterization of dual galectin-1 and -3 inhibition and the potential of this as an anti-cancer therapy.

Here, I will talk about stereoselective ‘trapping’ of NONO by covalent small molecules, leading to impaired maturation of associated oncogenic transcripts and suppression of cancer cell growth. Via this trapping model, these small molecules stabilize the interaction of NONO with its target mRNAs and circumvent the compensatory action of paralog proteins (SFPQ1, PSPC1) that otherwise offsets the genetic loss of NONO in knockout models. We conclude that NONO represents a druggable protein that can be targeted by covalent chemistry to suppress previously undruggable oncogenic pathways in cells.

Increased clinical use of BTK inhibitors has given rise to acquired resistance mutations in patients with B cell malignancies. Newly discovered kinase-dead BTK mutants have also revealed unexpected oncogenic scaffolding functions of BTK, requiring new approaches. Nurix’s clinical-stage BTK degraders NX-2127 and NX-5948 directly address emerging resistance mutations and BTK scaffolding activity. Biochemical, cellular, and structural characterizations have elucidated the mechanism underlying the potent and broad activity of these molecules.

WD40 repeat proteins constitute one of the largest protein families, characterized by 44-60 amino acid repeats terminating in tryptophan and aspartate (WD).  WD repeat proteins act as scaffolding proteins and play an important role in many cellular functions and as such have become an interesting family to drug. We will describe the discovery and optimization of small molecule binders to two members of this family (WDR5 and DCAF1).

We used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9+TREM2+ macrophage population to which we assign a profibrotic role across species and tissues, which are defined by expression of SPP1, GPNMB,FABP5, and CD63.  GM-CSF, IL-17A or TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers, and blockade of these cytokines reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis in mice.

Innate and therapy-induced resistance to checkpoint inhibitors limit the response rate in many cancers. An increased TGF-ß signature is linked to poor clinical outcomes and checkpoint resistance. avß8 controls localized and cell-type-specific activation of TGF-ß 1 and 3 to negatively regulate immunity and promotes tolerance. Selective avß8 inhibition is a safe and efficient approach to reverse TGF-ß-driven immunosuppression, improving anti-tumor adaptive immune responses and immune infiltration into the TME.

I will discuss how inhibition of avb8 and avb1 promote interferon gamma and suppresses TGFbeta signaling in tumors. Reprograming of tumor cytokine levels promotes proinflammatory cell infiltration and suppresses stromal protein synthesis. We found that treatment was synergistic with checkpoint inhibitors in multiple murine tumor models.