Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein-ligand complex X-ray structures, into a sub-μM, brain penetrant, HDAC2 inhibitor () capable of modulating histone acetylation levels .

Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 () through structure-guided optimization of our previously published isoindolinone lead ().

Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction.

Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent and inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

States as Activists.

Empowered to play a larger role in the delivery and administration of health care, a number of states are attempting to solve the pharmaceutical pricing crisis in creative and varied ways. This essay summarizes three particular states' more activist approaches, including states that have sought to empower their Medicaid programs to limit coverage of certain drugs based on price, attempted to use leverage to impose cost-efficiency requirements, and, in the most dramatic example, relied on new usage of "gouging" laws to bring down the costs of prescription drugs. Although all three approaches have met substantial resistance, they illustrate a new era of state experimentation in an effort to bring down the cost of prescription drugs.

A Farewell to Falsity: Shifting Standards in Medicare Fraud Enforcement.

For the better part of a decade, Americans have had a front-row seat to a fervent and turbulent debate over the future of their health care system. The passage of the Patient Protection and Affordable Care Act of 2010 (ACA), the most comprehensive health reform effort since the mid-1960s, ushered in a new era in health law and policy, granting millions of Americans access to health care. After multiple legal challenges and congressional efforts that ultimately failed to slay the law, the ACA had become entrenched by the end of the Obama administration, even though pieces of the law had failed to work exactly as planned.