Discovery and resistance mechanism of a selective CDK12 degrader

Jiang, Baishan; Gao, Yang; Che, Jianwei; Lu, Wenchao; Kaltheuner, Ines H.; Dries, Ruben; Kalocsay, Marian; Berberich, Matthew J.; Jiang, Jie; You, Inchul; Kwiatkowski, Nicholas; Riching, Kristin M.; Daniels, Danette L.; Sorger, Peter K.; Geyer, Matthias; Zhang, Tinghu; Gray, Nathanael S.

doi:10.1038/s41589-021-00765-y

“…Furthermore, the remarkably favourable PK profile of SIM1 suggests trivalent PROTACs will be appropriate for in vivo use despite their increased molecular weight. The enhanced potency and increased sites of binding of trivalent PROTACs might potentially allow to alleviate or circumvent some of the emerging cancer resistance mechanisms with monovalent and bivalent degraders, such as missense mutations on the target protein 46 .…”

Section: Resultsmentioning

confidence: 99%

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

Imaide

¹

,

Riching

²

,

Makukhin

³

et al. 2021

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Bivalent PROTACs work drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhanced degradation. Here, we designed trivalent PROTACs consisting of a bivalent BET inhibitor and an E3 ligand, tethered via a branched linker. We identified VHL-based SIM1 as a low picomolar BET degrader, with preference for BRD2. Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anti-cancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.

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“…with small-molecule catalytic inhibitors, it is necessary to address whether cancer cells could become resistant to PROTACs. For example, cancer cells can develop mutations that reduce the pharmacophore's binding affinity to its intended target (Lovly and Shaw, 2014;Torres-Ayuso and Brognard, 2019); consistent with this mechanism of resistance, mutations in the protein of interest can render it resistant to PROTAC-mediated degradation, as recently shown for CDK12 (Jiang et al, 2021). Nonetheless, because target degradation efficacy does not correlate with the PROTAC binding affinity to its target, PROTACs could still effectively degrade these novel variants.…”

Section: Besides the Pharmacological Properties Of Protacs And Based ...mentioning

confidence: 88%

Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer

Torres‐Ayuso

¹

,

Brognard

²

2022

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Amplification of pro-oncogenic kinases is a common genetic alteration driving tumorigenic phenotypes. Cancer cells rely on the amplified kinases to sustain cell proliferation, survival, and growth, presenting an opportunity to develop therapies targeting the amplified kinases. Utilizing small-molecule catalytic inhibitors as therapies to target amplified kinases is plagued by de novo resistance driven by increased expression of the target, and amplified kinases can drive tumorigenic phenotypes independent of catalytic activity. Here, we discuss the emergence of proteolysis-targeting chimeras that provide an opportunity to target these oncogenic drivers effectively. SignificanceProtein kinases contribute to tumorigenesis through catalytic and non-catalytic mechanisms, and kinase gene amplifications are well-described mechanisms of resistance to small-molecule catalytic inhibitors. Repurposing catalytic inhibitors for the development of protein degraders will offer improved clinical benefits by targeting non-catalytic functions of kinases that promote tumorigenesis and overcoming resistance due to amplification.

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“…The enhanced potency and increased sites of binding of trivalent PROTACs might potentially allow to alleviate or circumvent some of the emerging cancer resistance mechanisms with monovalent and bivalent degraders, such as missense mutations on the target protein 46 .…”

Section: Discussionmentioning

confidence: 99%

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

Imaide¹,

Riching²,

Makukhin³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Bivalent PROTACs work drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhanced degradation. Here, we designed trivalent PROTACs consisting of a bivalent BET inhibitor and an E3 ligand, tethered via a branched linker. We identified VHL-based SIM1 as a low picomolar BET degrader, with preference for BRD2. Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anti-cancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.

show abstract

Discovery and resistance mechanism of a selective CDK12 degrader

Cited by 90 publications

References 52 publications

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

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