Discovery of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimer\u27s disease.

Proteomic studies have identified moesin (MSN), a protein containing a four-point-one, ezrin, radixin, moesin (FERM) domain, and the receptor CD44 as hub proteins found within a coexpression module strongly linked to Alzheimer\u27s disease (AD) traits and microglia. These proteins are more abundant in Alzheimer\u27s patient brains, and their levels are positively correlated with cognitive decline, amyloid plaque deposition, and neurofibrillary tangle burden. The MSN FERM domain interacts with the phospholipid phosphatidylinositol 4,5-bisphosphate (PI

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC

Discovery of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimers disease.

Proteomic studies have identified moesin (MSN), a protein containing a four-point-one, ezrin, radixin, moesin (FERM) domain, and the receptor CD44 as hub proteins found within a coexpression module strongly linked to Alzheimers disease (AD) traits and microglia. These proteins are more abundant in Alzheimers patient brains, and their levels are positively correlated with cognitive decline, amyloid plaque deposition, and neurofibrillary tangle burden. The MSN FERM domain interacts with the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) and the cytoplasmic tail of CD44. Inhibiting the MSN-CD44 interaction may help limit AD-associated neuronal damage. Here, we investigated the feasibility of developing inhibitors that target this protein-protein interaction. We have employed structural, mutational, and phage-display studies to examine how CD44 binds to the FERM domain of MSN. Interestingly, we have identified an allosteric site located close to the PIP2 binding pocket that influences CD44 binding. These findings suggest a mechanism in which PIP2 binding to the FERM domain stimulates CD44 binding through an allosteric effect, leading to the formation of a neighboring pocket capable of accommodating a receptor tail. Furthermore, high-throughput screening of a chemical library identified two compounds that disrupt the MSN-CD44 interaction. One compound series was further optimized for biochemical activity, specificity, and solubility. Our results suggest that the FERM domain holds potential as a drug development target. Small molecule preliminary leads generated from this study could serve as a foundation for additional medicinal chemistry efforts with the goal of controlling microglial activity in AD by modifying the MSN-CD44 interaction

Compounds 13, 37, and 44 (100 μM) bind covalently to TBXT and MSN via mass spectrometry.

Number of mass adducts of the compound are indicated in red.</p

Compound 44 covalently modifies SYK-tSH2.

(A) Chemical structures of initial HTS hit 39 and analogue 43. (B) Synthesis of 44 from analogue 42. (C) Mass spectrometry of SYK-SH2 incubated with covalent inhibitor 1 and old versus fresh stocks of 42 and 43 at 100 μM for 1 h at room temperature. Only the old DMSO stock of 42 reacts covalently with SYK-tSH2. (D) Mass spectrometry of SYK-tSH2 incubated with 42 and 44 at 100 μM for 1 h at room temperature. I Dose-response of 44 in covalently labelling SYK-tSH2, assessed by mass spectrometry. (F) Dose response curve of 44 in the TR-FRET assay (IC50 = 0.27 ± 0.02 μM). (G) Hypothesized mechanism of inhibition of 44 with SYK-tSH2. (H) Compound 44 disrupted the PPI via GST-pulldown in a dose-response fashion. An unmodified blot corresponding with panel (H) is included in S7 Fig.</p

Biochemical and biophysical data for compounds 37, 13, 42, 43, and 44.

The estimated IC50 for GST-PD is calculated via the western blot densitometry. a Solubility calculated with a nephelometer (S5 Fig). b Kinetic solubility calculated by Analiza, Inc. An unmodified blot used to generate GST-PD IC50 values is included in S7 Fig.</p