A series of stable, small molecule compounds that inhibit an alternative (non-VEGF) angiogenic pathway that is overexpressed in a variety of cancers.
Background:
Antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway are widely used to treat solid tumors and ocular conditions such as wet AMD. However, anti-VEGF therapies face a fundamental limitation: therapy-induced hypoxia stimulates compensatory angiogenic pathways, diminishing efficacy over time and selecting for more invasive, metastasis-prone cancer cells. There is a critical unmet need for therapies that target these alternative pathways.
The apelin receptor (APJ) has emerged as one of the most promising such targets. A recent transcriptomic analysis across cancer types identified the APJ/apelin pair as the second most concordantly upregulated G protein-coupled receptor (GPCR) system in the tumor microenvironment. APJ is overexpressed in a wide variety of cancers—including those of the ovary, lung, breast, pancreas, kidney, and colon—and contributes to pathogenesis through angiogenesis, metastasis, and cell proliferation. In ovarian cancer specifically, apelin secreted from adipocytes increases lipid uptake in APJ-expressing cancer cells, providing metabolic support for metastatic survival. Elevated APJ expression correlates with poor prognosis across multiple cancer types. Importantly, anti-APJ therapy has been shown to improve the efficacy of immunotherapy in metastatic breast cancer, and when combined with anti-VEGF therapy, to reduce therapy-associated metastasis and normalize blood vessel structure for improved drug delivery into tumors.
Despite this compelling target biology, no viable anti-APJ drug candidates have advanced to clinical development. ML221, the only reported selective small molecule APJ antagonist, suffers from poor plasma and liver microsomal stability (half-life <10 min), precluding meaningful in vivo exposure. Peptide-based APJ antagonists (e.g., F13A and MM54) face similar limitations, including rapid proteolytic degradation and short half-lives. This gap between a well-validated target and the lack of drug-like molecules represents a significant commercial opportunity.
Technology Overview:
This invention provides a series of small molecule anti-APJ antagonists that overcome the key problems (metabolic instabilities and thus short plasma half-life) seen with ML221. First-generation leads demonstrated superior (>50% more than ML221) inhibition of cell migration. Building on these results, a second-generation series was developed using in silico metabolic site prediction and structure-guided design, yielding compounds with liver microsomal half-lives exceeding 60 minutes (vs. <10 min for ML221) and >25-fold greater systemic exposure. In an orthotopic ovarian cancer xenograft mouse model, the lead compound (YL-GB063) significantly increased median survival and reduced metastatic tumor burden and ascites formation compared to both control and ML221-treated groups.
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Artur, stock.adobe.com
Advantages:
Applications:
Intellectual Property Summary
Patent pending.
Stage of Development:
In vivo (orthotopic ovarian cancer xenograft model)
Licensing Status:
Available for licensing or collaboration.
Publication link(s):