Here, I will discuss a new targeted covalent inhibitor approach targeting histone acetyltransferases PCAF/GCN5, and nucleosome remodeling complex members, CECR2 and BPTF. A structure-based design approach has been guided by medicinal chemistry efforts targeting non-conserved nucleophilic amino acids in a flexible loop of the bromodomain binding pocket. Choice of electrophilic designs has imparted selectivity towards these bromodomain-containing proteins, leading to cell-active inhibitors and starting points for designing new proximity-inducing molecules.

KT-300 is a first-in-class covalent inhibitor of the E3 ubiquitin ligase TRIM7, a key effector downstream of RTK–KRAS signaling. By blocking hyperactivated TRIM7 in cancers with EGFR, KRAS, BRAF, or MEK alterations, KT-300 induces potent tumor growth inhibition. Kayak’s preclinical studies show superior efficacy to KRAS inhibitors and antibodies, with mutation-agnostic activity enabling broad targeting of RTK–KRAS–driven tumors.

We recently introduced PCIPs (PARP-based chemical inducers of proximity), which rewire chromatin-regulated DNA repair processes by recruiting BET proteins to PARP2. PCIPs are synthetically lethal to homologous recombination (HR)–deficient tumors and show increased toxicity to cancer cells that are resistant to conventional PARP inhibitors, presenting a promising new modality for therapeutic translation. More broadly, this class of compounds establishes an exciting new framework for probing and controlling DNA repair through proximity pharmacology.

The induced proximity landscape has exploded over the last several years with both academic and industry groups investigating various biological outcomes of linking two targeted warheads together. My presentation will focus on utilizing bifunctional molecules to specifically modulate transcriptional programs and signaling outcomes mediated by chromatin regulatory complexes. Our efforts reveal compounds which can either activate or repress transcription at specific loci or more broadly across the chromatin depending on the induced proximity pairings. This approach suggests a promising path forward for drug discovery to develop compounds which can be tailored for a variety of indications.

Pathological seeding of protein misfolding is a hallmark of proteinopathies. However, therapeutic strategies to clear these aggregates are lacking, impairing the study of their biological importance in disease etiology and the development of therapeutics. Our work describes a dopant system consisting of an engineered alpha-synuclein protein construct that rapidly co-aggregates into existing wild-type alpha-synuclein oligomers, enabling rapid degradation of the entire assembly in the presence of a small molecule trigger.

KRAS mutations drive tumorigenesis in cancers such as lung and pancreatic cancer. Autophagy supports tumor survival under metabolic stress, making it a promising therapeutic target in KRAS mutant tumors. ULK1 and ATG13 are core components of the complex that initiates autophagy. Using a HiBiT tagged ATG13 HTS assay, we identified SBP-1750, a ULK inhibitor that promotes ATG13 degradation, inhibits autophagy, suppresses tumor growth, and enhances anti tumor immunity in KRAS mutant cancer models.