med chem @ Arvinas | PhD @ Columbia | hiker | cocktail enthusiast | he/him/huz/dad | dreaming of Sedona | while I have a connection to Arvinas, all opinions expressed are my own and do not represent the views, opinions, or positions of the company
Keith Hornberger
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Folks - little help for my kid on his Sociology final project. If you’ve got a spare 1-2 minutes, please take his short survey on AI usage. Trying to help him get a sample of more than just HS kids.
Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors
Discovery and Evaluation of a PROTAC Degrader Targeting SAMHD1 for the Treatment of Pulmonary Fibrosis
Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome
Pine Knob Loop in Sharon, CT. In just 2.5 mi and a fairly challenging 710’ vertical, you get awesome views of the Litchfield Hills, a short sojourn on the AT, a (dry-ish) waterfall, mountain laurel in full bloom, and… 90 minutes of solitude to recharge.
From KRASG12D to Pan-KRAS Inhibitors─A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design
Hsp70-Targeting Chimeras Enable Dual Proteasomal and Lysosomal Degradation of Intracellular and Extracellular Proteins
New PROTAC Designs for Targeted Protein Degradation in 2021–2025: Novel E3 Ligases and Pre-PROTACs
A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader
Responses are anonymous; please answer as honestly as possible.
Oral bioavailability of PROTACs, which often fall outside the Rule-of-Five space, is still not perfectly understood. Thus, the design of orally bioavailable PROTACs remains challenging. Chameleonicity...
SAMHD1 regulates intracellular nucleotide pool composition, and its overexpression is linked to tumor resistance to nucleoside drugs, organ injury, and fibrosis. Existing SAMHD1 inhibitors only exhibi...
Targeted Protein Degradation (TPD) relies on the binding of specific targets and E3 ubiquitin-ligases to promote ubiquitination and degradation of targets by the proteasome. Here, by designing chimera...
KRAS, a significant oncology target, has been challenging to develop drugs for until recent discoveries of KRASG12C mutant-specific covalent inhibitors, including MK-1084. This article describes efforts toward the discovery of KRASG12D mutant-specific inhibitors and how synthetic innovations and structure-based drug design were utilized to facilitate the discovery of pan-KRAS inhibitors.
Developing targeted protein degradation (TPD) strategies with disease-specific mechanisms, modularity, and facile designability could ensure drug efficacy and selectivity. Herein, a small-molecule, Hs...
Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative paradigm in pharmaceutical research. Despite significant progress in PROTACs, they are overwhelmingly dominated by the recruitment of a very restricted subset of canonical E3 ligases (e.g., CRBN and VHL), which hinders their potential therapeutic applications. As a result, recent developments have led to the emergence of PROTACs that utilize nonclassical E3 ligases. Another challenge is systemic toxicity caused by degradation on-target degradation in nonintended tissues, prompting the development of pre-PROTACs to achieve conditional and spatiotemporal modulation of target protein levels. Herein, we provide a comprehensive summary and discussion of recent advancements in PROTACs based on “novel” E3 ligases, as well as PROTAC prodrugs activated by external stimuli and the tumor microenvironment, highlighting prospects for the design of effective and selective PROTACs.
IMiD-based PROTACs may degrade IKZF1/3 with hematologic effects. This study profiles these liabilities using hematopoietic assays showing stem cell rewiring and interferon activation and introduces a ...
