Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

Zeng, Mei; Xiong, Yuning; Safaee, Nozhat; Nowak, Radosław P.; Donovan, Katherine A.; Yuan, Christine J.; Nabet, Behnam; Gero, Thomas W.; Feru, Frédéric; Li, Lianbo; Gondi, Sudershan; Ombelets, Lincoln J.; Quan, Chunshan; Jänne, Pasi A.; Kostić, Milka; Scott, David A.; Westover, Kenneth D.; Fischer, Eric S.; Gray, Nathanael S.

doi:10.1016/j.chembiol.2019.12.006

Cited by 210 publications

(213 citation statements)

References 75 publications

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“…Since PROTACs often exhibit poor cell‐penetration due to their high molecular weight and presence of many hydrogen bond acceptors and donors, we sought to evaluate cellular permeability and intracellular CRBN engagement using a previously described cellular assay . Briefly, this is a competition‐based assay that measures the ability of a degrader molecule to displace BRD4 BD2 ‐directed CRBN ligands, which subsequently leads to the restoration of BRD4 BD2 ‐GFP signal.…”

Section: Resultsmentioning

confidence: 99%

Mutant‐Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug‐Resistant Mutations

Jang

Clercq

et al. 2020

Angewandte Chemie

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Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug‐resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC‐01‐163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC‐01‐163 is also effective against osimertinib‐resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP‐site EGFR inhibitor, osimertinib, the anti‐proliferative activity of DDC‐01‐163 against L858R/T790M EGFR‐Ba/F3 cells is enhanced. Collectively, DDC‐01‐163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP‐site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.

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Section: Resultsmentioning

confidence: 99%

Mutant‐Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug‐Resistant Mutations

Jang

Clercq

et al. 2020

Angewandte Chemie

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“…Using an overexpressed and tagged construct of the target proteins allows easy monitoring (e.g. GFP tagged proteins), quick setup and time resolved degradation in a high throughput format but due to potential high expression levels weak degraders might be missed or false positive PROTACs identified which only initiate degradation of the tag instead of the target protein itself . CRISPR/Cas modifications of the endogenous target protein adding a small tag (HA‐tag or NanoLuc®) are more time consuming but can increase sensitivity due to endogenous protein levels and a more favorable target protein/E3 ligase ratio.…”

Section: Degradation Of Untagged Target Proteinsmentioning

confidence: 99%

Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective

et al. 2020

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Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created tremendous excitement in chemical biology and drug discovery within the past decades. The TPD field is spearheaded by small molecule induced protein degradation with molecular glues and proteolysis targeting chimeras (PROTACs) paving the way to expand the druggable space and to create a new paradigm in drug discovery. However, besides the therapeutic angle of TPD a plethora of novel techniques to modulate and control protein levels have been developed. This enables chemical biologists to better understand protein function and to discover and verify new therapeutic targets. This Review gives a comprehensive overview of chemical biology techniques inducing TPD. It explains the strengths and weaknesses of these methods in the context of drug discovery and discusses their future potential from a medicinal chemist's perspective.

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“…A key challenge in PROTAC design to date is the selection of the optimal linker to connect these two binding components. In most cases, linkers of various lengths are screened using synthetically accessible chemistry [15][16][17][18][19] . In some cases, it was shown that a protein-protein interface between the target and the E3 ligase, including interactions with the linker, is important for cooperativity 4 .…”

Section: Introductionmentioning

confidence: 99%

PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes

Zaidman

London

2020

Preprint

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Proteolysis-targeting chimeras (PROTACs), which induce degradation by recruitment of an E3 ligase to a target protein, are gaining much interest as a new pharmacological modality. However, designing PROTACs is challenging. Formation of a ternary complex between the protein target, the PROTAC and the recruited E3 ligase is considered paramount for successful degradation. A structural model of this ternary complex could in principle inform rational PROTAC design. Unfortunately, only a handful of structures are available for such complexes, necessitating tools for their modeling. We developed a combined protocol that alternates between sampling of the protein-protein interaction space and the PROTAC molecule conformational space. Application of this protocol -PRosettaC -to a benchmark of known PROTAC ternary complexes results in near-native predictions, with often atomic accuracy prediction of the protein chains, as well as the PROTAC binding moieties. It allowed the modeling of a CRBN/BTK complex that recapitulated experimental results for a series of PROTACs. PRosettaC generated models may be used to design PROTACs for new targets, as well as improve PROTACs for existing targets, potentially cutting down time and synthesis efforts.

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Exploring Targeted Degradation Strategy for Oncogenic KRASG12C

Abstract: Highlights d A comprehensive degrader molecule (PROTAC) library for KRAS G12C is described d Lead compound degrades GFP-KRAS G12C in a CRBNdependent manner d Challenges and solutions for achieving endogenous KRAS G12C degradation are discussed

Cited by 210 publications

References 75 publications

Mutant‐Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug‐Resistant Mutations

Mutant‐Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug‐Resistant Mutations

Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective

PRosettaC: Rosetta based modeling of PROTAC mediated ternary complexes

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