I present our BBO-10203 compound, an orally available drug candidate which binds covalently and specifically to the RAS-binding domain of PI3K-alpha kinase and prevents activation by KRAS, inhibiting tumor growth in mutant KRAS or PIK3CA driven tumors. Unlike other PI3K inhibitors, BBO-10203 does not provoke hyperglycemia as insulin signaling does not rely on RAS proteins to activate glucose uptake pathways.

KRAS is one of the most frequently mutated oncogenes in human cancers. Our medicinal chemistry effort guided by experiences in the development of sotorasib (KRAS G12Ci) and structure/property-based design principles led to the identification of AMG 410, an orally bioavailable, reversible pan-KRAS inhibitor. AMG 410 is highly selective against both HRAS and NRAS, and is a dual GTP(on)- and GDP(off)-state inhibitor. AMG 410 showed good preclinical efficacy and tolerability.

NRX-0305 is an orally bioavailable pan-mutant BRAF degrader that selectively targets Class 1/2/3 mutations while sparing wildtype BRAF. It potently degrades mutant BRAF, suppresses ERK signaling, and synergizes with MEK inhibitors, yielding robust anti-tumor activity in vitro and in vivo, including BRAF inhibitor–resistant and brain metastasis models. Mutant BRAF degradation, alone or in combination with existing agents, may overcome key limitations of current therapies for diverse BRAF-driven cancers.

MOMA-341 is a chemically distinct, potent and selective clinical stage covalent inhibitor of WRN. Leveraging MOMA's KNOWMATIC platform and the presence of cysteine 727 in an allosteric binding pocket, covalent inhibitors were designed to achieve high potency.  Optimization was based on precise refinement of covalent warhead trajectory, compound rigidity, and improvement of binding affinity to drive high kinact/KI.  Optimization of potency and ADME properties, guided by in silico prediction of in vivo target occupancy, led to the discovery of MOMA-341, which demonstrates tumor regression at low doses in MSI-H mouse xenograft models and is in clinical development.

Werner Syndrome helicase (WRN) targets mismatch repair deficiency in cancer cells, making it a key target for MSI-H or MMRd tumors. In this presentation, we will describe the identification of a novel allosteric binding pocket using fragment-based screening. Moreover, we will discuss in more detail the chemical progression of one of the fragments hit and underscore the challenges faced in targeting this dynamic helicase.

I describe how we engineer precisely tuned, stabilized helical peptide therapeutics to unlock traditionally undruggable targets. I focus on using our helicons to eliminate disease-driving proteins, including those that small molecule glues and degraders cannot access. A wide range of ligands for E3 ligases can be incorporated as amino acid side chains on a Helicon.

Monovalent degraders are molecules that can induce target degradation without containing known ligase binding motifs. As the rules by which these molecules can induce degradation are poorly understood, they are typically found serendipitously. I will describe a systematic drug discovery campaign that led to a potent monovalent degrader of BRM, an important lung cancer target. Furthermore, I will show that this molecule works by covalently recruiting the ligase FBX022.

CREB binding protein (CBP) and E1A binding protein P300 (EP300) are paralog lysine acetyltransferases that function as transcriptional coactivators. Their bidirectional synthetic lethal relationship creates a unique therapeutic opportunity for selectively targeting CBP in EP300-mutant cancers. We demonstrate the potent antiproliferative activity of our selective CBP degraders, both as single agents and in the context of select combination therapies.

Proteolysis-targeting chimera (PROTAC) that selectively eliminates detrimental proteins represents a promising therapeutic strategy for various diseases. We have developed a set of PROTACs with the short and interchangeable degradation signals that attract several distinct E3 ubiquitin ligases. We demonstrate the utility and efficacy of these mini-PROTACs in vitro and in vivo against several oncogenic drivers, expanding the repertoire of limited ligands and degradation pathways available for PROTACs.

The MALT1 paracaspase is constitutively activated in various B cell malignancies by chronic stimulation of the B cell receptor or through gain-of-function mutations in upstream components of the NF-kB pathway. ABBV-525 allosterically inhibits MALT1 and has potent preclinical activity as a monotherapy or bolsters combination therapeutics in models of non-Hodgkin’s lymphoma. ABBV-525 is an investigational drug currently in Phase I clinical studies for the treatment of B cell malignancies.

FORX-428 is a potent and orally bioavailable inhibitor of poly(ADP-ribose) glycohydrolase (PARG), a key enzyme in the DNA damage response. Inhibition of PARG by FORX-428 leads to PAR chain accumulation, inducing replication stress and tumor cell death. The compound exhibits strong, reversible binding to PARG, selective cytotoxicity across different cancer cell lines, and robust anti-tumor efficacy in xenograft models, demonstrating best-in-class potential among PARG and PARP inhibitors.

MTAP-deleted cancers accumulate of MTA, partially inhibits PRMT5, creating a vulnerability. We identified AM-9959, a side product of DEL91, bound to the PRMT5:MEP50+MTA complex, forming an inhibitory ternary complex. Subsequent optimization of AM-9959 led to AM-9747. AM-9747 selectively inhibited PRMT5 dimethylation, thereby reducing viability in MTAP-deleted cells. AM-9747 was well tolerated and effectively inhibited arginine dimethylation and tumor growth in MTAP-deleted tumors without impacting the growth of MTAP-WT tumors. This presentation will also cover: DEL Synthesis, Hit Validation and Hit Optimization.

Acrivon’s Predictive Precision Proteomics (AP3) platform enables biological SAR for optimal drug design through global pathway insights into drug activity and resistance mechanisms. AP3 powered the discovery of ACR-2316, a novel, potent WEE1/PKMYT1 inhibitor. Through dual WEE1/PKMYT1 inhibition, combined with strong PLK1 activation, ACR-2316 induces apoptotic cancer cell death with complete tumor regression in mice. ACR-2316 is advancing in a Phase 1 clinical trial in AP3-prioritized solid tumor types.