Identification of PDE6D as a potential target of sorafenib via PROTAC technology

Yang, Li; Meng, Qingshi; Wang, Ping; Fu, Qiuyu; Xie, Yuting; Zhou, Yu; Qi, Xiangbing; Huang, Niu

doi:10.1101/2020.05.06.079947

Cited by 10 publications

(12 citation statements)

References 33 publications

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“…, BRD9). PROTAC is not only an emerging drug discovery modality but also offers new chemical tools for target identification and validation and for deciphering target biology. , For example, PROTAC-mediated degradation can reveal the noncatalytic activity of protein kinases. , Herein, we report the discovery and characterization of XL01126, a von Hippel–Lindau (VHL)-based, fast, potent, cooperative, and selective LRRK2 PROTAC degrader that is also orally bioavailable and blood–brain barrier (BBB)-permeable. XL01126 qualifies as a chemical probe to study LRRK2 biology, further validate the target as a therapeutic concept in PD, and usher in future drug development.…”

Section: Introductionmentioning

confidence: 99%

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

et al. 2022

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Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most promising targets for Parkinson's Disease. LRRK2 targeting strategies have primarily focused on Type 1 kinase inhibitors, which however have limitations as the inhibited protein can interfere with natural mechanisms which could lead to undesirable side effects. Herein, we report the development of LRRK2 Proteolysis Targeting Chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2 targeting strategy. Initial designs and screens of PROTACs based on ligands for E3 ligases von Hippel-Lindau (VHL), Cereblon (CRBN), and cellular inhibitor of Apoptosis (cIAP) identified the best degraders containing thioetherconjugated VHL ligand VH101. A second round of medicinal chemistry exploration led to qualifying XL01126 as a fast and potent degrader of LRRK2 in multiple cell lines, with DC50 values within 15-72 nM, Dmax values range from 82-90%, and degradation half-lives span from 0.6h to 2.4h. XL01126 exhibits high cell permeability and forms a positively cooperative ternary complex with VHL and LRRK2 (α=5.7), which compensates for a substantial loss of binary binding affinities to VHL and LRRK2, underscoring its strong degradation performance in cells. Remarkably, XL01126 is orally bioavailable (F=15%) and can penetrate the blood brain barrier after either oral or parenteral dosing in mice. Taken together, these experiments qualify XL01126 as a suitable degrader probe to study non-catalytic and scaffolding functions of LRRK2 in vitro and in vivo and offer an attractive starting point for future drug development.

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Section: Introductionmentioning

confidence: 99%

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

et al. 2022

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“…The proteomic data also revealed a small (~30%) depletion in protein levels of phosphodiesterase 6d (PDE6D) (Figure 11). PDE6D has a deep hydrophobic ligand-binding pocket, and has been shown to be degradable via PROTACs 43,69 Curiously, PDE6D was also found as adventitious off-target degradation of PTK2 PROTACs previously 70 . Inspection of chemical structures highlighted that the PTK2 PROTAC and XL01126 share a similar aminopyrimidine warhead at the target ligand end, a moiety known to be critical to the high binding affinity in PDE6D inhibitor Deltasonamide 69 , suggesting a potential off-target degradation due to adventitious PROTAC binding to PDE6D.…”

Section: Xl01126 Induces Cooperative Ternary Complex Formationmentioning

confidence: 99%

“…BRD9). PROTAC is not only an emerging drug discovery modality but also offers new chemical tools for target identification and validation, and for deciphering target biology 43,44 . For example, PROTAC-mediated degradation can reveal non-catalytic activity of protein kinases 45,46 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Oral bioavailable and Blood Brain Barrier Penetrant PROTAC Degrader of Leucine Rich Repeat Kinase 2 (LRRK2)

Liu

Kalogeropulou

Domingos

et al. 2022

Preprint

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Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most promising targets for Parkinson’s Disease. LRRK2 targeting strategies have primarily focused on Type 1 kinase inhibitors, which however have limitations as the inhibited pro-tein can interfere with natural mechanisms which could lead to undesirable side effects. Herein, we report the devel-opment of LRRK2 Proteolysis Targeting Chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2 targeting strategy. Initial designs and screens of PROTACs based on ligands for E3 ligases VHL, CRBN and cIAP identified the best degraders containing thioether-conjugated VHL ligand VH101. A second round of medicinal chemistry exploration led to qualifying XL01126 as a fast and potent degrader of LRRK2 in multiple cell lines, with DC50 values within 15-72 nM, Dmax values range from 82-90%, and degradation half-lives span from 0.6h to2.4h. XL01126 exhibits high cell permeability and forms a positively cooperative ternary complex with VHL and LRRK2 (α=5.7), which compensates for a substantial loss of binary binding affinities to VHL and LRRK2, underscoring its strong degradation performance in cells. Remarkably, XL01126 is orally bioavailable (F=15%) and can penetrate the blood brain barrier after either oral or parenteral dosing in mice. Taken together, these experiments qualify XL01126 as a suitable degrader probe to study non-catalytic and scaffolding functions of LRRK2 in vitro and in vivo and offer an attractive starting point for future drug development.

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“…Furthermore, pharmacological, proteasome-mediated selective degradation of RAF1 by means of proteolysis-targeting chimeras (PROTAC) could lead to another strategy in specifically targeting RAF1 ( 134 ). To date, however, RAF1 degradation by PROTACs has noy yet been successfully tested ( 135 , 136 ).…”

Section: The Ras-raf-mek-erk Signaling Cascade In Oncogene-driven Tum...mentioning

confidence: 99%

Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation

et al. 2022

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Hyperactivation of the RAS-RAF-MEK-ERK cascade - a mitogen-activated protein kinase pathway – has a well-known association with oncogenesis of leading tumor entities, including non-small cell lung cancer, colorectal carcinoma, pancreatic ductal adenocarcinoma, and malignant melanoma. Increasing evidence shows that genetic alterations leading to RAS-RAF-MEK-ERK pathway hyperactivation mediate contact- and soluble-dependent crosstalk between tumor, tumor microenvironment (TME) and the immune system resulting in immune escape mechanisms and establishment of a tumor-sustaining environment. Consequently, pharmacological interruption of this pathway not only leads to tumor-cell intrinsic disruptive effects but also modification of the TME and anti-tumor immunomodulation. At the same time, the importance of ERK signaling in immune cell physiology and potentiation of anti-tumor immune responses through ERK signaling inhibition within immune cell subsets has received growing appreciation. Specifically, a strong case was made for targeted MEK inhibition due to promising associated immune cell intrinsic modulatory effects. However, the successful transition of therapeutic agents interrupting RAS-RAF-MEK-ERK hyperactivation is still being hampered by significant limitations regarding durable efficacy, therapy resistance and toxicity. We here collate and summarize the multifaceted role of RAS-RAF-MEK-ERK signaling in physiology and oncoimmunology and outline the rationale and concepts for exploitation of immunomodulatory properties of RAS-RAF-MEK-ERK inhibition while accentuating the role of MEK inhibition in combinatorial and intermittent anticancer therapy. Furthermore, we point out the extensive scientific efforts dedicated to overcoming the challenges encountered during the clinical transition of various therapeutic agents in the search for the most effective and safe patient- and tumor-tailored treatment approach.

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Identification of PDE6D as a potential target of sorafenib via PROTAC technology

Cited by 10 publications

References 33 publications

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Oral bioavailable and Blood Brain Barrier Penetrant PROTAC Degrader of Leucine Rich Repeat Kinase 2 (LRRK2)

Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation

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