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Medicinal Chemistry Project Leader

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Targeting Multiple KRAS Mutations with High-Affinity Macrocyclic Inhibitors: From Discovery to Preclinical Validation

Abstract. The RAS Switch-II pockets’ discovery enabled targeting a challenging molecular site. Covalent KRASG12C inhibitors inspired efforts to find compou

pubs.acs.org

Antibody-Mediated Delivery of BRM/BRG1 Protein Degraders Affords Strong Antitumor Efficacy in Multiple BRM-Dependent Non-Small Cell Lung Cancer Xenograft Models

Abstract. The synthesis and biological characterization of multiple degrader antibody conjugates (DACs) bearing a heterobifunctional VHL-dependent proteoly

pubs.acs.org

Identification and SAR optimization of FBXO22-mediated TEAD Targeted Glue™ degraders

TEAD transcription factors are emerging oncology targets due to their function as key effectors of the Hippo signalling pathway, which is frequently dysregulated in cancer. Here, we report the discove...

biorxiv.org

Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation - Nature Chemical Biology

The authors identified a series of covalent, monovalent glue degraders that can co-opt two E3 ligases, DCAF16 and FBXO22, in a parallel fashion to degrade SMARCA2/4 and demonstrated that ligase prefer...

nature.com

Interface Architecture of a VHL-PROTAC Complex with and without Cullin-2

Abstract. Proteolysis Targeting Chimeras (PROTACs) are bispecific molecules that link a target protein to an E3 ligase, leading to ubiquitination and subse

pubs.acs.org

Discovery of molecular glues that bind FKBP12 and structurally distinct targets using DNA-encoded libraries - Nature Communications

In this study, authors screen a 3.2 million member FKBP scaffold-directed DNA-encoded library and identify FKBP12-binding molecular glues for both bromodomain-containing protein 9 (BRD9) and quinoid d...

nature.com

Harnessing FBXO31 with Terminal Amide-Functionalized Molecules for Targeted Protein Degradation

Abstract. Targeted protein degradation (TPD) is a powerful strategy for controlling protein abundance. Here, we establish FBXO31 as a TPD-competent E3 liga

pubs.acs.org

Identification of E3 ligase substrates and PROTAC-induced ubiquitylation sites using proximity-based identification of ubiquitin sites (PrIUS) - Communications Biology

Proximity-dependent biotinylation coupled with ubiquitin remnant enrichment identifies PROTAC-induced ubiquitylation sites and E3 ligase substrates.

nature.com

Bellerophon: An Automated Tool for PROTAC Decomposition

Proteolysis-targeting chimeras (PROTACs) represent a promising modality for targeted protein degradation, yet their structural complexity complicates systematic design and analysis. Bellerophon is a n...

pubs.acs.org

The Contribution of Native Protein Complexes to Targeted Protein Degradation

Targeted protein degradation (TPD) destroys proteins of interest (POIs) by hijacking the cellular proteolytic machinery. Most proteins in cells exist and function as part of multiprotein or macromolecular complexes, thereby allowing a single protein to control multiple biological processes. Therefore, when a small molecule degrader induces the proximity between an E3 ligase and the POI, the macromolecular context of the POI potentially influences the degradation outcomes of the POI and of the complex components. Here, we explore the degradation of the eight CK1α-SACK1 (formerly known as FAM83A-H) complexes initiated by molecular glue degraders primarily designed to target Ser/Thr kinase CK1α. We demonstrate that lenalidomide-derived degraders DEG-77 and SJ3149, which selectively target the CK1α isoform, codegrade multiple SACK1 proteins. We show that the degradation of SACK1 proteins by DEG-77 and SJ3149 requires CK1α, the CUL4ACRBN E3 ligase complex, and the proteasome. In cells derived from palmoplantar keratoderma patients harboring the CK1α-binding-deficient SACK1GR265P mutation, DEG-77 targets CK1α and mitotic SACK1D but not SACK1GR265P, highlighting the requirement for CK1α-SACK1 interaction to achieve codegradation. Our study underscores the importance of POI context in TPD and reinforces the potential for selectively targeting specific protein complexes for degradation.

pubs.acs.org

From KRASG12D to Pan-KRAS Inhibitors─A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design

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.

pubs.acs.org

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New PROTAC Designs for Targeted Protein Degradation in 2021–2025: Novel E3 Ligases and Pre-PROTACs

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.

pubs.acs.org

Discovery and Evaluation of a PROTAC Degrader Targeting SAMHD1 for the Treatment of Pulmonary Fibrosis

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...

pubs.acs.org

Evaluation of Oral PROTAC Guidelines: Efflux Ratio Outweighs Chameleonicity Descriptors

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...

pubs.acs.org

Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome - Nature Communications

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...

nature.com

Hsp70-Targeting Chimeras Enable Dual Proteasomal and Lysosomal Degradation of Intracellular and Extracellular Proteins

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...

pubs.acs.org

A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader - Nature Communications

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 ...

nature.com