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Phenotypic screening provides compounds with very limited target cellular localization data. In order to select the most appropriate target identification methods, determining if a compound acts at the cell-surface or intracellularly can be very valuable. In addition, controlling cell-permeability of targeted therapeutics such as antibody-drug conjugates (ADCs) and targeted nanoparticle formulations can reduce toxicity from extracellular release of drug in undesired tissues or direct activity in bystander cells. By incorporating highly polar, anionic moieties via short polyethylene glycol linkers into compounds with known intracellular, and cell-surface targets, we have been able to correlate the cellular activity of compounds with their subcellular site of action. For compounds with nuclear (Brd, PARP) or cytosolic (dasatinib, NAMPT) targets, addition of the permeability modifying group (small sulfonic acid, polycarboxylic acid, or a polysulfonated fluorescent dye) results in near complete loss of biological activity in cell-based assays. For cell-surface targets (H 3 , 5HT 1A , β 2 AR) significant activity was maintained for all conjugates, but the results were more nuanced in that the modifiers impacted binding/activity of the resulting conjugates. Taken together, these results demonstrate that small anionic compounds can be used to control cell-permeability independent of on-target activity and should find utility in guiding target deconvolution studies and controlling drug distribution of targeted therapeutics.

Study Design: This study analyzed the anatomic relation of the dorsal ramus of the cervical spinal nerve to the lateral mass., Objectives: To determine the location of the dorsal rami of the cervical spinal nerves from C3 to C7 in relation to the superior articular processes of the lateral masses., Summary of Background Data: The anatomic study of the cervical spinal nerve and its relations to adjacent bony structures have been addressed. No previous anatomic study with regard to the location of its dorsal ramus relative to the lateral mass has been reported., Methods: Twelve specimens were obtained for study of the dorsal rami of the cervical spinal nerves. All soft tissues surrounding the cervical spinal nerves from C3 to C7 were dissected from the intervertebral foramens until the dorsal rami were clearly exposed. The facet joints in the corresponding levels were then opened by removal of the capsules. Three measurements, including the height of the dorsal ramus, the distance between the dorsal ramus and the tip of the superior articular facet, and the angle of the dorsal ramus relative to the superior articular surface, were taken for each ramus., Results: The results showed that the mean height of the dorsal ramus for both sides decreased progressively from C3 (2.2 +/- 0.6 mm) to C7 (1.2 +/- 0.2 mm). The mean distance between the dorsal ramus and the tip of the superior facet showed an inconsistent change, with the maximum value seen at C5 (7.4 +/- 1.6 mm) and the minimum at C7 (5.5 +/- 2.9 mm). The mean angle of the dorsal ramus relative to the superior articular facet ranged from 23.3 degrees +/- 14.3 degrees to 29.8 degrees +/- 11.2 degrees., Conclusions: The dorsal ramus of the cervical spinal nerve is closer to the anterolateral corner of the base of the superior articular processes. Lateral mass screws directed to the anterolateral corner of the base of the superior articular process should be avoided.