Z-4169252340

While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.

A chem. fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1) as a potential 4R-tau binding ligand.Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [³H]1 provided K_D (nM) values in AD = 4.0, PSP = 5.1, and CBD = 4.5.In vivo positron emission tomog. (PET) imaging in rats with [¹⁸F]1 demonstrated good brain penetration and rapid clearance from normal brain tissues.A subsequent mol. similarity search using 1 as the query revealed an addnl. promising compound, Z4169252340 (4-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)morpholine; 21).Binding assays with [³H]21 provided K_D (nM) values in AD = 1.2, PSP = 1.6, and CBD = 1.7 and lower affinities for binding aggregated α-synuclein and amyloid-beta.PET imaging in rats with [¹⁸F]21 demonstrated a higher brain penetration than [¹⁸F]1 and rapid clearance from normal brain tissues.We anticipate that 1 and 21 will be useful for the identification of other potent novel 4R-tau radiotracers.