Development of a RIPK1 degrader to enhance antitumor immunity

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Дек. 16, 2024

Abstract The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by poorly defined binding pocket within intermediate domain RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology develop RIPK1 degrader, LD4172. LD4172 exhibits potent selective degradation both in vitro vivo. Degradation triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, sensitizes tumors anti-PD1 therapy female C57BL/6J mice. This work reports degrader that serves chemical probe investigating functions potential therapeutic agent enhance tumor responses ICBs therapy.

Язык: Английский

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RIPK1 is essential for Herpes Simplex Virus-triggered ZBP1-dependent necroptosis in human cells

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 19, 2024

Abstract Necroptosis initiated by the host sensor Z-NA Binding Protein-1 (ZBP1) is essential for defense against a growing number of viruses, including Herpes Simplex Virus-1 (HSV-1). Studies with HSV-1 and other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers necroptosis directly complexing kinase RIPK3. Whether this also case human cells, or whether additional co-factors are needed ZBP1-mediated necroptosis, unclear. Here, we show ZBP1-induced cells requires RIPK1. We found RIPK1 forming stable functional ZBP1-RIPK3 complex but dispensable formation equivalent complex. The RIP Homology Interaction Motif (RHIM) RIPK3 responsible difference between two species, because replacing RHIM from sufficient to overcome requirement cells. These observations describe critical mechanistic mice humans how engages important implications treating diseases.

Язык: Английский

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RIPK1: Inflamed if you do, inflamed if you don’t

Immunity, Год журнала: 2024, Номер 57(7), С. 1443 - 1445

Опубликована: Июль 1, 2024

Язык: Английский

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Targeted Degradation of Receptor-Interacting Protein Kinase 1 to Modulate the Necroptosis Pathway

ACS Pharmacology & Translational Science, Год журнала: 2024, Номер 7(11), С. 3518 - 3526

Опубликована: Окт. 15, 2024

Necroptosis is a highly regulated form of necrotic cell death that plays an essential role in pathogen defense and tissue homeostasis. Abnormal regulation the necroptotic pathway has been implicated pathogenesis various human diseases, including cancer, inflammatory, neurodegenerative diseases. Receptor-interacting protein kinase 1 (RIPK1) serves as crucial regulator signaling identified potential therapeutic target. Mechanistically, RIPK1 both scaffolding protein, fulfilling its dual function through combination activity-dependent activity-independent mechanisms. Thus, employing targeted knockdown strategy effective means inhibiting functions. To achieve knockdown, we generated RIPK1-PROTAC, MS2031, by connecting ZB-R-55 binder to VHL ligand, thereby recruiting CUL2-RING-VHL (CRL2

Язык: Английский

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RIPK1 inhibition in malignant cells potentiates immunotherapy and radiotherapy outcome

OncoImmunology, Год журнала: 2024, Номер 13(1)

Опубликована: Ноя. 4, 2024

Apoptosis, necroptosis and pro-inflammatory NF-κB-dependent signaling are repressed by receptor-interacting serine/threonine-protein kinase 1 (RIPK1). A recent paper in Immunity describes a small molecule inducing the proteolytic degradation of RIPK1. In preclinical experiments, this RIPK1 inhibitor improved anticancer efficacy radiotherapy, immunotherapy (with PD-1 blockade) radioimmunotherapy CTLA-4 blockade).

Язык: Английский

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PTGES3 proteolysis using the liposomal peptide-PROTAC approach

Biology Direct, Год журнала: 2024, Номер 19(1)

Опубликована: Дек. 26, 2024

Язык: Английский

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