The CBL-B E3 ubiquitin ligase functions as a negative regulator of T cell receptor activation. We report discovery of NX-1607, an orally bioavailable CBL-B inhibitor that demonstrates anti-tumor activity in multiple preclinical tumor models. NX-1607 triggers rapid NK and T cell infiltration of tumors and shows increased frequency of tumor rejection in combination with anti-PD-1. Our studies provide rationale for clinical development of NX-1607 in advanced malignancies.

Casitas B-lineage lymphoma-b (CBL-B) is a member of the CBL family of RING E3 ubiquitin ligases. CBL-B negatively regulates T cell receptor signaling and T cell activation and its inhibition leads to immune activation. This makes CBL-B an attractive target for cancer immunology, with inhibitors having the potential to be broadly active in multiple oncology indications. Here we discuss the use of biochemical, biophysical, and cellular assays, for hit finding and lead development, applied to identifying and developing CBL-B inhibitors with isoform selectivity and cellular potency.

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.

MALT1 has a central role in the integration of the B cell signaling pathway, and therapeutic targeting of this protease has generated interest for the treatment of aggressive lymphomas. We will present the discovery of ABBV-MALT1, a potent and selective inhibitor of MALT1. Further, we will illustrate the observed mechanistic rationale for synergy between ABBV-MALT1 and the BCL2 inhibitor venetoclax. This combination results in superior efficacy in models of aggressive lymphoma.

The innate immune system, in particular the cytosolic DNA sensing cGAS-STING pathway plays a crucial role in host defense via the induction of type I interferon (IFN). However, inappropriate activation of the cGAS-STING signaling pathway, as seen in familial SAVI mutations, could lead to life-threatening disease. Newly developed STING agonist and antagonist compounds offer hope for patients suffering from certain types of cancers and autoinflammatory diseases.

The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising approach for the treatment of cancers associated with a dysregulation of the Hippo pathway. Starting from a weakly active hit binding to one of the two main sites of interaction of YAP at the surface of TEAD, we managed to improve the potency of this hit class by several orders of magnitude, and to identify inhibitors with cellular activity, which displayed efficacy in tumor-bearing mice after oral administration. The main features of this work will be presented finally leading to the discovery of our clinical compound NVP-IAG933.

We newly identified the gene Metastasis associated in colon cancer 1 (MACC1). This gene induces cancer cell proliferation, motility and metastasis in mice. Here we introduce the audience into novel options for development of anti-metastatic therapy strategies by using repurposed small molecule drugs and novel compounds for cancer metastasis inhibition.

MALDI imaging mass spectrometry (IMS) was used to quantify the distribution of a STING (stimulator of interferon genes) agonist under early discovery in liver collected from a mouse model after oral dosing. The parent drug was detected with a zonal distribution localized in the portal triad, specifically localized to the cellular populations in the sinusoids including the target cellular population Kupffer cells. A series of drug-related metabolites was detected to localize in the central zones. The study exemplified that multiple pharmacokinetic properties of a drug can be characterized with spatial context by MALDI IMS.

Retinoic acid inducible gene (RIG-I) plays a central role in the induction of innate immune response. We have developed a new class of Stem-loop RNA compounds as novel RIG-I agonists that are being advanced as anticancer agents and broad-spectrum antivirals. The activation of RIG-I induces interferon signaling cascade for tumor killing through apoptosis of tumors and the induction of innate and adaptive immune responses. The lead compound shows potent antitumor activity in multiple syngeneic tumor models when used alone and in combination with other agents, with the induction of adaptive immune response, abscopal effects and immune memory.

Transcription factors are known to bind to cereblon in the presence of molecular glues and some reports implicate interactions with multiple zinc fingers. We present biophysical and structural assessments of the minimal binding domains of IKZF2 and another transcription factor revealing that two zinc fingers interact with cereblon:glue complexes. In these examples, the binding modes are distinct and may have implications for the design of selective degraders.

IKZF2 (Helios) plays an important role in maintaining stability and function of regulatory T cells (Tregs). Proteovant applied a structure-guided drug discovery approach to identify an IKZF2 selective molecular glue degrader, PVTX-405. PVTX-405 shows selective degradation of IKZF2 in vitro and in vivo. PVTX-405 treatment reduces suppressive activity of human Treg cells ex vivo and delays growth of MC38 tumors in immune competent mice in vivo.

The Jian Jin Laboratory at Mount Sinai is a leader in discovering novel degraders targeting oncogenic proteins and developing new technologies for advancing the targeted protein degradation field. Our lab’s recent progress advancing the targeted protein degradation, including TF-PROTAC, Bridged PROTAC, Folate-caged PROTAC, opto-PROTAC, and KEAP1-recruiting PROTAC technologies will be presented.

STAT (signal transducer and activator of transcription) proteins are a family of transcription factors that mediate signal transduction downstream of cytokine and growth factor receptors. Hyperactivation of STAT3 and STAT5 has been linked to cancer cell proliferation, survival, stemness, and immune evasion, making them attractive targets for cancer therapy. STATs have been difficult to target by traditional small-molecule inhibitors. Employing the PROTAC technology, we have developed highly selective and potent STAT3 or STAT5 degraders with strong anti-tumor activities in hematologic cancer models.