Lori Capone

Bio: Lori Capone is an academic researcher from Celgene. The author has contributed to research in topics: Pomalidomide & Apremilast. The author has an hindex of 7, co-authored 13 publications receiving 770 citations.

Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.

Abstract: Background and purpose: Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis.

Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration

Abstract: Purpose To investigate the pharmacokinetics and disposition of [14C]pomalidomide following a single oral dose to healthy male subjects

Disposition, metabolism and mass balance of [14C]apremilast following oral administration

Abstract: Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis. The pharmacokinetics and disposition of [14C]apremilast was investigated following a single oral dose (20 mg, 100 μCi) to healthy male subjects.Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean Cmax, AUC0–∞ and tmax values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h. Apremilast was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and 4% of the excreted radioactivity were O-demethylated apremilas...

Psoriasis Pathogenesis and Treatment.

Abstract: Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.

Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide

Abstract: In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Abstract: The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma

Abstract: Immunomodulatory drugs (IMiDs) are thalidomide analogues, which possess pleiotropic anti-myeloma properties including immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. Their development was facilitated by an improved understanding in myeloma (MM) biology and initiated a profound shift in the therapeutic approach towards MM. Despite the diverse effects of IMiDs in vitro, the relative contribution of each effect towards their ultimate anti-MM activity is still unclear. Based on in vitro data, it appears that anti-proliferative effects and downregulation of crucial cytokines are their most important anti-MM attributes. Although the co-stimulatory effects on T and NK cells have been heralded as a unique and important property of IMiDs towards enhancing anti-MM immune activity, these in vitro effects have yet to be firmly corroborated in vivo. Much is yet to be elucidated regarding the complex interplay of immunomodulatory cytokines that occurs in vivo, which ultimately dictates the net effects of IMiDs in MM—the understanding of which is necessary to facilitate optimal manipulation of these drugs in future MM management.