Keith Hornberger

Also it’s apparently the first day of dirt bikes popping wheelies on New Haven city streets season. No quads traveling in packs yet, but soon 🏍️

Welcome to pothole season

Discovery and Optimization of Orally Bioavailable Heterobifunctional Degraders of KAT2A/B for the Treatment of Cancer Using our proprietary AI/ML platform AURIGIN that maps tumor cells against normal developmental pathways, we identify targets that have been hijacked by cancerous cells to maintain a highly plastic proliferative cell state. We identified the histone acetyltransferase KAT2A as a key driver of tumor cell plasticity in a subset of acute myeloid leukemias (AML) and neuroendocrine carcinomas such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Herein, we describe our development of heterobifunctional degraders of KAT2A/B, resulting in compound 7, a picomolar degrader that is capable of inhibiting proliferation of AML (MOLM-13) and SCLC (NCI–H1048) cell lines in vitro and demonstrates robust degradation of KAT2A in NCI–H1048 engrafted mice when administered IP. Building on the success of compound 7, we subsequently developed orally bioavailable degraders of KAT2A/B, exemplified by compound 24, that achieved an oral bioavailability of 47% in mice.

Discovery and Optimization of Orally Bioavailable Heterobifunctional Degraders of KAT2A/B for the Treatment of Cancer

Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation Proteolysis-targeting chimeras (PROTACs) have transformed the concept of chemical intervention in biological systems by co-opting the ubiquitin–proteasome system to selectively degrade proteins. A key...

Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation

Benchmarking Deep Learning for PROTAC Ternary Complex Prediction Proteolysis Targeting Chimeras (PROTACs) represent a transformative approach to drug development by leveraging the intracellular ubiquitin-proteasome system (UPS) for the selective degradation of tar...

Benchmarking Deep Learning for PROTAC Ternary Complex Prediction

The Affinity Advantage Drug discovery is a complex, multiparameter optimization process. I argue that a greater emphasis on optimizing binding affinity will accelerate drug discovery. Note that “optimizing” is not always sy...

The Affinity Advantage

Happy first day of meteorological spring to all those who celebrate

An Update on Clinically Advanced PROTAC Degraders and Their Synthesis

Unhooking the Hook: Optimization of the Aurora A Targeting PROTAC JB170 to CCT400028, an In Vitro Degrader Chemical Probe Proteolysis TArgeting Chimeras (PROTACs) can be used to target both the catalytic and noncatalytic functions of a protein, which can be particularly beneficial for proteins with important scaffolding ...

Unhooking the Hook: Optimization of the Aurora A Targeting PROTAC JB170 to CCT400028, an In Vitro Degrader Chemical Probe

Design, synthesis and biological evaluation of macrocyclic NTRK heterobifunctional degraders Aberrant NTRK gene fusions leading to constitutively activated NTRK proteins are a key driver for a range of adult and pediatric tumors. Small molecul…

Design, synthesis and biological evaluation of macrocyclic NTRK heterobifunctional degraders

Current snowstorm vibes

For me it’s an Industry Sour, which is an equal parts witches brew of Fernet Branca, green Chartreuse, lime juice, and simple syrup, which somehow works.

My wife asked for “something with gin” tonight so I made the Army & Navy, which is basically a gin sour with orgeat instead of simple and a splash of Angostura bitters. Cheers friends!

Discovery and Characterization of a First-In-Class HCK/BTK PROTAC DFCI-002-06 for the Treatment of MYD88 Mutated B Cell Malignancies Hematopoietic cell kinase (HCK) and Bruton tyrosine kinase (BTK) are critical drivers of survival signaling in MYD88-mutated (MYD88Mut) lymphomas. Building on our previously developed dual HCK/BTK inh...

Discovery and Characterization of a First-In-Class HCK/BTK PROTAC DFCI-002-06 for the Treatment of MYD88 Mutated B Cell Malignancies

Direct-to-Biology Enabled Molecular Glue Discovery Molecular glues powerfully control protein proximity but have largely eluded direct screening. A promising avenue for addressing this challenge lies within pinpointing the fundamental features for function-first identification of molecular gluing events. In the widely accepted mechanism, a molecular glue stabilizes two proteins within a ternary complex─here, we show how differences in affinity for ternary and binary complexes directly categorize glues from nonglues. We leverage these differences together with high-throughput chemical synthesis and affinity-selection mass-spectrometry to discover a molecular glue from a suite of over 20,000 crude chemical reaction mixtures. Orthogonal assays robustly support the identification of molecular glues via ternary complex stability. Our findings suggest that a roadmap for de novo molecular glue discovery lies within kinetic profiling of unpurified mixtures of small organic molecules against protein pairs.

Direct-to-Biology Enabled Molecular Glue Discovery

A Facile Protocol for C(sp2)–C(sp3) Bond Formation Reactions Toward Functionalized E3 Ligase Ligands A robust C(sp2)–C(sp3) decarboxylative coupling strategy enables access to new CRBN ligands and degraders with improved physicochemical properties. This synthetic approach is expanding the chemical s...

A Facile Protocol for C(sp2)–C(sp3) Bond Formation Reactions Toward Functionalized E3 Ligase Ligands

Discovery and Characterization of Novel BLIMP-1 Heterobifunctional Ligand-Directed Degraders B-lymphocyte-induced maturation protein 1 (BLIMP-1/PRDM1) is a master transcriptional repressor essential for terminal differentiation of activated B-cells into bone-marrow resident plasma cells. Mult...

Discovery and Characterization of Novel BLIMP‑1 Heterobifunctional Ligand-Directed Degraders

Second-Generation AURKA-Targeting PROTACs: Structural Optimization toward in Vivo Degradation in Neuroblastoma Aurora kinase A (AURKA) is an established oncogenic factor and therapeutic target in neuroblastoma due to its roles in mitosis and stability of the MYCN protein. We previously identified SK2188 as a h...

Second-Generation AURKA-Targeting PROTACs: Structural Optimization toward in Vivo Degradation in Neuroblastoma

Developmental toxicology profile of the IRAK4 degrader KT-474 Abstract. KT-474 is a first-in-class IRAK4 heterobifunctional degrader that utilizes cereblon (CRBN) for E3 ligase recruitment and was rationally designed

Developmental Toxicology Profile of the IRAK4 Degrader KT-474

Recent advances in glutarimide chemistry for cereblon-mediated targeted protein degradation: developments in synthesis and diversification The field of targeted protein degradation has garnered significant attention over the past two decades, highlighted by the FDA approval of several therapeutics and the entry of numerous drug candidate...

Recent advances in glutarimide chemistry for cereblon-mediated targeted protein degradation: developments in synthesis and diversification

Development of Cathepsin B-Responsive GalNAc-PROTACs for Hepatocyte-Targeting Protein Degradation Targeted protein degradation (TPD) has arisen as a therapeutic revolution for eliminating disease-relevant proteins, but its tissue-specific delivery remains a critical challenge. Here, we developed an asialoglycoprotein receptor (ASGPR)-based platform for the selective degradation of target proteins in hepatocytes. By conjugating the ASGPR ligand triantennary N-acetylgalactosamine (tri-GalNAc) with a BRD4-targeted proteolysis targeting chimera (PROTAC) via a cathepsin B (CTSB)-cleavable Val-Cit-PABC linker, we generated a prototype GalNAc-PROTAC conjugate, TMU454. TMU454 selectively degraded BRD4 in ASGPR-positive hepatocellular carcinoma cells while sparing ASGPR-negative cancer cells and normal cells. Mechanistic investigations confirmed that TMU454-mediated BRD4 degradation is dependent on the ASGPR-mediated endocytosis, CTSB-mediated linker cleavage, and ubiquitin-proteasome system (UPS). Furthermore, a fluorescein-labeled analogue, TMU670, revealed preferential liver accumulation. Importantly, TMU454 significantly inhibited tumor growth in a Huh7-derived liver cancer xenograft model without apparent systemic toxicity. Collectively, this study establishes a versatile approach for tissue-selective protein degradation and advances targeted therapies for liver cancer.

Development of Cathepsin B-Responsive GalNAc-PROTACs for Hepatocyte-Targeting Protein Degradation

Doesn’t use the center letter

All TACs are out apparently

😢

Conformational Dynamics in the Cell Membrane Interactions of Bispecific Targeted Degrader Therapeutics Proteolysis targeting chimeras (PROTACs) offer vast new therapeutic opportunities, but their physicochemical properties are difficult to combine with optimal cell permeability and exposure at the targ...

Conformational Dynamics in the Cell Membrane Interactions of Bispecific Targeted Degrader Therapeutics

Interstate Love Song is now Muzak at the grocery store and readers I cannot

Have been fighting off a cold most of the last two weeks and haven’t had much energy or bandwidth for posting stuff, but hoping to get back on the wagon next week. It felt amazingly good to be well enough to do a workout this morning. 🏃‍♂️🏋️‍♀️

Happy New Year 2026 from Aruba! Bon voyage, 2025 - not gonna miss you too much. 🏝️ 🎇

If you’re looking for me I’ll be in the Caribbean 🏝️

Selective CDK6 Degradation via the KLHDC2 E3 Ubiquitin Ligase We discovered novel small molecule ligands of KLHDC2 and leveraged them to generate KLHDC2-mediated CDK6-selective degraders. Degrader 48a exhibited potent and selective CDK6 degradation (DC50 = 0.037...

Selective CDK6 Degradation via the KLHDC2 E3 Ubiquitin Ligase