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.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell signaling. Upon T cell receptor (TCR) stimulation, activated HPK1 phosphorylates the adaptor protein SLP76, triggering its degradation and downregulating T cell functions needed for effective anti-tumor immune responses. We present our efforts on the development of pyrazolopyrimidines as potent and selective inhibitors of HPK1 along with descriptions of their pharmacological profiles in in vivo PD and efficacy models.

The E3 ubiquitin ligase CBL-B is expressed in multiple immune cell lineages and is a master regulator of immune response. NX-1607 is a molecule that glues CBL-B into an inactive conformation lowering the threshold for T cell activation. In cancer models, NX-1607 inhibits tumor growth when dosed orally. We present preclinical data on NX-1607, supporting its advancement to clinical testing, and pharmacokinetic-pharmacodynamic (PK-PD) data from the FIH trial (NCT05107674).

Diacylglycerol lipase (DAGL) a and ß convert diacylglycerols into monoacylglycerols including the endocannabinoid 2-arachidonoylglycerol (2-AG). Arachidonic acid (AA) derived from 2-AG can be further metabolized into proalgesic and proinflammatory eicosanoids. Inhibition of DAGLs has been explored as a mechanism distinct from NSAIDs to reduce eicosanoid production. However, disruption of DAGLa activity in the brain reduces neuronal 2-AG-mediated endocannabinoid signaling leading to detrimental effects. Leveraging chemoproteomic methods, a medicinal chemistry campaign identified A1480LS as a covalent, peripherally distributing small molecule inhibitor of DAGLa/ß that reduces pain-behavior in animals. Thus, we offer an improved strategy to target DAGLs to treat chronic pain.

We designed the first Brd4-BD2-selective inhibitor, which we are developing for inflammatory diseases. BET was an oncology therapeutic target until efficacy and tox concerns became evident. Pan-BD2 BET inhibitors have shown in vivo anti-inflammatory activity in multiple preclinical models, but similar concerns over thrombocytopenia have stifled development of non-selective BET inhibitors. By sharing our selective BETi program success, we hope to motivate others to pursue epigenetic regulators outside of oncology.

TippingPoint’s novel platform targets the entire network of defective interactions in the cancer genome state rather than a single factor. Our approach increases specificity, reducing toxicity, and is robust against single-factor mutagenesis, reducing drug resistance. TippingPoint’s platform will provide new therapies to treat cancers with poor prognosis and limited treatment options, such as glioblastomas and lung cancers.

Adenosine receptor signaling contributes to acquired resistance to PD-1/PD-L1 blockade. Studies have shown that the concurrent administration of PD-1/PD-L1 checkpoint inhibitors along with A2AR antagonists is more effective than single-agent treatments for anti-tumor efficacy. We have discovered small molecule inhibitors that dually target PD-L1 and A2AR. These inhibitors exhibit desirable drug-like properties and demonstrate significant tumor growth inhibition in syngeneic tumor models that correlates with potent immune activation.

The transcription factor hypoxia-inducible factor 2a (HIF-2a) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Hypoxic or pseudohypoxic conditions promote HIF-2a stabilization and transcription of pro-tumorigenic genes. Inhibition of HIF-2a has significant potential to mitigate tumor growth, particularly in cancers with a high prevalence of molecular alterations associated with pseudohypoxia. Herein, we describe the discovery and optimization of a potent series of small molecule HIF-2a inhibitors.

This is the first disclosure of a small molecule inhibitor of ADAR1. We report that ADAR1 (adenosine deaminase RNA), an RNA editing enzyme, has promising anti-tumor efficacy as monotherapy and in combination with other modalities. Herein, we outline the discovery of a potential first-in-class ADAR1 p150 inhibitor for cancer immunotherapy.

We developed a potent and specific RIPK1 degrader, LD4172, that synergizes with anti-PD1 to trigger immunogenic cell death and significantly inhibit tumor growth in immunotherapy-resistant syngeneic mouse models. The synergistic effect of LD4172 and anti-PD1 can be reversed by blocking either CD19, BAFFR, CD8, or CD40L, demonstrating that both B and T cells and their crosstalk play important roles in the antitumor immunity.

An important challenge for ligase-based targeted protein degradation (TPD) is identifying new ligands for existing ligases. Because ubiquitin ligases are usually part of a multi-subunit protein that contains one or more binding partners, hit-finding assays need to differentiate binding locations. To identify new chemotypes for the VHL and cereblon ligases, we used various hit finding methods including fragment screening. I will describe our results and the complexities we encountered.

A fragment-based screening strategy was employed to identify allosteric binders for tau tubulin kinase 1 (TTBK1). Several hit classes identified by leveraging biophysical, computational, and crystallographic approaches were prioritized based on the biophysical profile, potential ligandability, and potential of binding site for inhibitory selectivity. The identified allosteric pockets and corresponding fragment hits will be discussed with regard to their potential and early elaboration to provide kinome selectivity for TTBK1.