双功能PARP和HDAC抑制剂kt-3283的脂质纳米颗粒制剂的开发

Poly(ADP-ribose) polymerase (PARP) plays a major role in DNA repair and PARP inhibitors (PARPi) have shown clinical benefit in a number of tumor indications. Deacetylation of histones, controlled by histone deacetylases (HDACs) is a key regulatory event in DNA repair and inhibition of HDACs has been shown to reduce tumor growth in vitro and in vivo . PARPi combined with HDAC inhibition has demonstrated enhanced efficacy in pre-clinical studies in various tumor indications, and in patients with metastatic breast cancer. However, combination therapies can be limited in clinical utility due to overlapping toxicities and different pharmacokinetic profiles. kt-3283 embodies synthetic lethality by integrating two synergistic mechanisms-PARP inhibition and HDAC-mediated chromatin remodeling-into a single compound thereby eliminating the need for simultaneous or staggered drug combination regimens and the risk of overlapping toxicities. Previous studies have demonstrated strong inhibition of PARP1/2 and HDAC enzymes in vitro , inhibition of cell cycle arrest and DNA damage marker upregulation, significant inhibition of cell viability across multiple tumor types, and inhibition of metastatic seeding in an ex vivo pulmonary metastasis assay. While kt-3283 has demonstrated potent anti-tumor activity in vitro, its clinical viability is limited by low bioavailability and poor metabolic stability. Lipid nanoparticles (LNPs) are nanocarriers for oncology drugs, offering superior encapsulation efficiency, with the ability to incorporate hydrophobic and hydrophilic payloads, protecting them from degradation and targeting for tumor selectivity. Patterned LNPs (pLNPs) designed using the EnsaliX AI platform are novel class of LNPs enable superior targeting, stability and safety through highly ordered structures. Kt-3283 is being encapsulated into the EnsaliX-designed pLNPs to produce pLNP/kt-3283. Physicochemical parameters of kt-3283 (solubility, pKa, thermal behavior, and metabolic stability) are being integrated for optimal pLNP/kt-3283 fabrication supporting enhanced encapsulation efficiency, and superior in vitro cell uptake, stability and bioavailability. Development of pLNP/kt-3283 uniquely combines design, formulation, and evaluation of a DDR-targeting compound, overcoming metabolic instability, and off-target limitations, and improving the therapeutic index.