Navitoclax
Navitoclax is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax.
Mechanism of action
In addition to Bcl-2, navitoclax also inhibits the related Bcl-xL and Bcl-w proteins. Because navitoclax inhibits Bcl-xL, it reduces platelet lifespan, causing thrombocytopenia, and this makes it dose-limiting. A 2020 article published in Aging Cell details the synthesis of Nav-Gal, a novel prodrug via galacto-conjugation of navitoclax and its superiority. The prodrug reduces thrombocytopenia in treated mice at therapeutically effective doses, as well as apoptosis of platelets in human blood samples treated ex vivo. Nav-Gal is efficient for selective senolysis and is passively taken up by both non-senescent and senescent cells.Effects against senescent cells
In animal studies, navitoclax was found to be a senolytic agent, inducing apoptosis in senescent, but not non-senescent cells. Oral administration of navitoclax to either sublethally irradiated or normally aged mice reduced senescent cells, including senescent bone marrow hematopoietic stem cells and senescent muscle stem cells. This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated the aged hematopoietic stem cells and muscle stem cells in normally aged mice.On September 19, 2018, an article was published in Nature about using navitoclax to kill senescent glial cells in mice. The drug had a protective effect against memory loss in mice genetically engineered to simulate Alzheimer's disease.
On December 3, 2024, an article was published in Aging detailing a study investigating the effects of topical navitoclax on aged mouse skin. It examined whether eliminating senescent cells could improve wound healing. In the study, 24-month-old mice were treated with topical navitoclax for five days. The treatment reduced the expression of senescence markers p16 and p21 and decreased the number of SA-β-gal– and p21-positive cells compared with DMSO controls. Navitoclax application also induced a transient inflammatory response and macrophage infiltration. Bulk RNA sequencing revealed upregulation of genes involved in wound-healing pathways, including inflammation, angiogenesis, collagen synthesis, and extracellular matrix remodeling. Mice pre-treated with navitoclax exhibited faster wound closure, suggesting that topical senolytic treatment may enhance skin repair by reducing senescent cell burden.
Clinical trials
The drug is currently under development by AbbVie.Navitoclax is used as mono-therapy as well as in combination with chemotherapies, olaparib, erlotinib, venetoclax, and rituximab in advanced hematological malignancies and solid tumors including ovarian cancer, breast cancer, lung cancer.
Additionally, an ongoing global multi-center, randomized, open-label, phase 3 study evaluating efficacy and safety of navitoclax in combination with ruxolitinib versus best available therapy in adult patients with relapsed/refractory myelofibrosis was initiated on 31 August 2020. The study is expected to conclude in 2026.