Studies on CD38 Inhibitors and Their Application to cADPR-Mediated Ca&lt;SUP&gt;2&lt;/SUP&gt;&lt;SUP&gt;+&lt;/SUP&gt; Signaling

Liu, Zhenming; Graeff, Richard; Jin, Hongwei; Zhang, Liangren; Zhang, Lihe

doi:10.1166/msr.2013.1017

Cited by 6 publications

(9 citation statements)

References 63 publications

(80 reference statements)

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“…To date, over 200 compounds are listed as CD38 inhibitors in the literature [40, 54, 58-60, 65-78]. Regarding chemical structures, CD38 inhibitors can be classified as NAD-analogs, flavonoids and heterocycles compounds [40, 54, 60, 65-78]. Based on mechanisms of action, they can be pooled into two groups: covalent and non-covalent inhibitors (Table 2).…”

Section: Pharmacological Approaches To Target/modulate Cd38mentioning

confidence: 99%

The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging

Chini

Netto

et al. 2018

Trends in Pharmacological Sciences

166

193

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Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein CD38 (cluster of differentiation 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, CD38 has been implicated in the regulation of metabolism and in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation. Interestingly, many of these functions are mediated by CD38 enzymatic activity. In addition, CD38 has also been identified as a cell-surface marker in hematologic cancers such as multiple myeloma, and a cytotoxic anti-CD38 antibody has been approved by the FDA for use in this disease. Although this is a remarkable development, killing CD38-positive tumor cells with cytotoxic anti-CD38 antibodies is only one of the potential pharmacological uses of targeting CD38. The present review discusses the biology of the CD38 enzyme and the current state of development of pharmacological tools aimed at CD38, and explores how these agents may represent a novel approach for treating human conditions including cancer, metabolic disease, and diseases of aging.

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Section: Pharmacological Approaches To Target/modulate Cd38mentioning

confidence: 99%

The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging

Chini

Netto

et al. 2018

Trends in Pharmacological Sciences

166

193

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“… 17 The emerging role of CD38 in disease states is stimulating the search for modulators of activity for chemical biological studies and to provide structural clues for drug design and potential therapeutic candidates. 18 To date, CD38 inhibitors fall broadly into two categories: mechanism-based covalent inhibitors that bind to the catalytic residue, and reversible, competitive, noncovalent inhibitors. Most are derived from NAD + and designed as inhibitors of the predominant NADase activity of CD38.…”

Section: Introductionmentioning

confidence: 99%

Cyclic Adenosine 5′-Diphosphate Ribose Analogs without a “Southern” Ribose Inhibit ADP-ribosyl Cyclase–Hydrolase CD38

et al. 2014

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Cyclic adenosine 5′-diphosphate ribose (cADPR) analogs based on the cyclic inosine 5′-diphosphate ribose (cIDPR) template were synthesized by recently developed stereo- and regioselective N1-ribosylation. Replacing the base N9-ribose with a butyl chain generates inhibitors of cADPR hydrolysis by the human ADP-ribosyl cyclase CD38 catalytic domain (shCD38), illustrating the nonessential nature of the “southern” ribose for binding. Butyl substitution generally improves potency relative to the parent cIDPRs, and 8-amino-N9-butyl-cIDPR is comparable to the best noncovalent CD38 inhibitors to date (IC50 = 3.3 μM). Crystallographic analysis of the shCD38:8-amino-N9-butyl-cIDPR complex to a 2.05 Å resolution unexpectedly reveals an N1-hydrolyzed ligand in the active site, suggesting that it is the N6-imino form of cADPR that is hydrolyzed by CD38. While HPLC studies confirm ligand cleavage at very high protein concentrations, they indicate that hydrolysis does not occur under physiological concentrations. Taken together, these analogs confirm that the “northern” ribose is critical for CD38 activity and inhibition, provide new insight into the mechanism of cADPR hydrolysis by CD38, and may aid future inhibitor design.

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“…The small molecule inhibitors can be categorized into two groups, covalent and non-covalent inhibitors (also known as irreversible and reversible inhibitors, respectively (Z. Liu, et al, 2013). The covalent group of inhibitors (also known as mechanism based inhibitors) take advantage of the catalytic mechanism of CD38 to form a covalent bond with the active site glutamic acid at position 226 of human CD38 (Sauve & Schramm, 2002).…”

Section: Design and Characterization Of Cd38 Inhibitorsmentioning

confidence: 99%

“…However, considering issues with stability and membrane permeability of the covalent inhibitors, it is thought that the non-covalent inhibitors will be better for future development as therapeutics and research tools (Z. Liu, et al, 2013; S. Zhang, et al, 2015).…”

Section: Design and Characterization Of Cd38 Inhibitorsmentioning

confidence: 99%

CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets

Deshpande

Guedes

Lund

et al. 2017

Pharmacology & Therapeutics

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CD38 is an ectoenzyme that catalyzes the conversion of β-nicotinamide adenine dinucleotide (β-NAD) to cyclic adenosine diphosphoribose (cADPR) and adenosine diphosphoribose (ADPR) and NADP to nicotinic acid adenine dinucleotide phosphate (NAADP) and adenosine diphosphoribose-2’-phosphate (ADPR-P). The metabolites of NAD and NADP have roles in calcium signaling in different cell types including airway smooth muscle (ASM) cells. In ASM cells, inflammatory cytokines augment CD38 expression and to a greater magnitude in cells from asthmatics, indicating a greater capacity for the generation of cADPR and ADPR in ASM from asthmatics. CD38 deficient mice develop attenuated airway responsiveness to inhaled methacholine following allergen sensitization and challenge compared to wild-type mice indicating its potential role in asthma. Regulation of CD38 expression in ASM cells is achieved by mitogen activated protein kinases, specific isoforms of PI3 kinases, the transcription factors NF-κB and AP-1, and post-transcriptionally by microRNAs. This review will focus on the role of CD38 in intracellular calcium regulation in ASM, contribution to airway inflammation and airway hyperresponsiveness in mouse models of allergic airway inflammation, the transcriptional and post-transcriptional mechanisms of regulation of expression, and outline approaches to inhibit its expression and activity.

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Studies on CD38 Inhibitors and Their Application to cADPR-Mediated Ca<SUP>2</SUP><SUP>+</SUP> Signaling

Cited by 6 publications

References 63 publications

The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging

The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging

Cyclic Adenosine 5′-Diphosphate Ribose Analogs without a “Southern” Ribose Inhibit ADP-ribosyl Cyclase–Hydrolase CD38

CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets

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