PTC-209

Cancer stem cells (CSCs) play critical roles in tumor growth, metastasis, and chemoresistance. Although several small-molecule inhibitors designed to inhibit CSCs have been investigated in clinical trials, their inadequate tumor targeting and potential off-target side effects have led to poor outcomes. A CD44-targeted virus-mimicking nanomedicine encapsulating the BMI1 inhibitor PTC209 (PTC209@VNP-HA) was designed to treat head and neck squamous cell carcinoma (HNSCC). We used a dendritic mesoporous silica nanoparticle (MSN) as the core for virus-mimicking nanoparticle (VNP) formation after adding shell particles to the MSN surface. The VNP surface was then modified with hyaluronic acid (HA), and PTC209 was adsorbed by mesopores to form PTC209@VNP-HA. In this system, HA is used to target CD44⁺ CSCs. The rough surface of VNP-HA provided better drug delivery efficiency than smooth nanoparticles modified with HA. VNP-HA enhanced the cancer inhibitory effect of PTC209 12-fold compared to the administration of free PTC209, leading to significantly higher bioavailability of PTC209. Both in vitro and in vivo assays showed that PTC209@VNP-HA inhibited cancer stemness, proliferation, and metastasis in HNSCC. Mechanistically, this inhibitory effect is closely associated with DNA damage/apoptosis signaling. Using a series of preclinical models in murine systems, we confirmed that PTC209@VNP-HA eliminated BMI1⁺ CSCs, and greatly inhibited the proliferation and metastasis of HNSCC when combined with cisplatin. This study investigated PTC209@VNP-HA as a novel and potentially transformative HNSCC treatment option that eliminates CSCs, prevents metastasis, and overcomes cisplatin resistance.

Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC₅₀ of 4.78 ± 0.08 μM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC₅₀ of 0.48 ± 0.02 μM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.