Development of Highly Potent Inhibitors of the Ras‐Targeting Human Acyl Protein Thioesterases Based on Substrate Similarity Design

Hedberg, Christian; Dekker, Frank J.; Rusch, Marion; Renner, Steffen; Wetzel, Stefan; Vartak, Nachiket; Gerding-Reimers, Claas; Bon, Robin S.; Bastiaens, Philippe I. H.; Waldmann, Herbert

doi:10.1002/ange.201102965

Cited by 21 publications

(33 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, the compounds also seem to exert only a static effect on parasite growth, which is consistent with their temporary inhibitory activity as shown previously (58).…”

Section: Resultssupporting

confidence: 90%

“…Thus, ␤-lactones 1-3 are selective small molecule inhibitors that behave as slowly converted, apparently competitive substrates and thus temporarily inhibit the APT enzyme activity. Compound 1 has been shown to inhibit hAPT1/2 selectively compared with other intracellular phospholipases such as phospholipases A 1 , A 2 , C␤, and D. For the ␤-lactones, compounds 1 and 2 are highly potent inhibitors of hAPTs, whereas compound 3 is the enantiomer of compound 2, which shows an order of magnitude lower potency in a biochemical assay using recombinant hAPT1 (57,58).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of a Serine Hydrolase Targeted by Acyl-protein Thioesterase Inhibitors in Toxoplasma gondii

Kemp

Rusch²,

Adibekian

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: S-Palmitoylation is an important reversible modification that involves the action of an acyl-protein thioesterase (APT). Results:We identified an active serine hydrolase (TgASH1) specifically targeted by human APT1 inhibitors in Toxoplasma gondii. Conclusion: TgASH1 is dispensable and cannot be solely responsible for S-depalmitoylation in Apicomplexa. Significance: ␤-Lactone-based APT1 inhibitors hit multiple targets in T. gondii and severely compromise parasite survival.

show abstract

“…Interestingly, the compounds also seem to exert only a static effect on parasite growth, which is consistent with their temporary inhibitory activity as shown previously (58).…”

Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Characterization of a Serine Hydrolase Targeted by Acyl-protein Thioesterase Inhibitors in Toxoplasma gondii

Kemp

Rusch²,

Adibekian

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…[1][2][3] Dynamic S-palmitoylation and S-depalmitoylation of H-and N-Ras by palmitoyl transferases and thioesterases determines proper Ras localization and signaling in cells. [4] Interference with the Ras-de/reacylation cycle by inhibition of the depalmitoylation through the use of the b-lactone acyl protein thioesterase 1 (APT1) inhibitors palmostatin B [5] or palmostatin M [6] ( Figure 1) disturbs the precise H-and N-Ras steady-state localization, and results in down-regulation of global Ras signaling. Palmostatin B does not inhibit several phosphodiesterases with relevance to Ras signaling.…”

mentioning

confidence: 99%

Identification of Acyl Protein Thioesterases 1 and 2 as the Cellular Targets of the Ras‐Signaling Modulators Palmostatin B and M

et al. 2011

Self Cite

View full text Add to dashboard Cite

show abstract

“…Newer and more potent inhibitors in this chemical series were reported recently, although systemic toxicities have not been fully described. 85 Blocking growth-promoting signals that converge to activate GEFs is another potential therapeutic strategy for treating cancers characterized by NRAS/KRAS/NF1 mutations. In the case of oncogenic Ras, this raises the question of whether these proteins are truly "constitutively active" or remain dependent on guanine nucleotide exchange for transforming activity.…”

Section: Therapeutic Strategies For Inhibiting Ras Processing and Actmentioning

confidence: 99%

Targeting oncogenic Ras signaling in hematologic malignancies

Ward

Braun

Shannon

2012

Blood

188

156

View full text Add to dashboard Cite

Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ϳ 25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanismbased therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer. (Blood. 2012;120(17): 3397-3406) IntroductionAberrant signal transduction resulting in reduced dependence on growth factors and other extracellular stimuli for the survival and proliferation of malignant cells is an established "hallmark of cancer." 1 RAS genes encode a family of 21-kDa proteins that are central nodes in signaling networks that regulate cell fate in many tissue lineages. RAS genes are also the most common targets of dominant somatic mutations in human cancer. 2,3 The high prevalence of mutations in NRAS, KRAS, and molecules, such as CKIT, PTPN11, CBL, and BCR-ABL1, that interact with Ras biochemically strongly implicate aberrant Ras signaling as an important therapeutic target in these cancers. [4][5][6][7] In this review, we focus on the pathobiology of mutations in hematologic cancers involving the "core" Ras-GTPase activating protein (GAP) complex, which includes Ras itself, guanine nucleotide exchange factors, and GAPs. At this writing, mutations in NRAS, KRAS, and the NF1 tumor suppressor, which encodes a GAP called neurofibromin, 8 are strongly associated with myeloid malignancies. Increasing evidence also implicates these genes as "drivers" in lymphoid cancers with "high-risk" clinical features. No mechanism-based treatments exist for the ϳ 25% of human cancers with KRAS or NRAS mutations or for the growing number of malignancies showing NF1 inactivation, and we discuss potential therapeutic strategies for addressing the adverse biochemical consequences of aberrant Ras signaling. Structural and functional properties of the Ras GTPase switchRas proteins are signal switch molecules that regulate cell fates by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. 9 On ligand binding, molecules, such as Shc, Grb2, Gab2, and SHP-2, are recruited to growth factor receptors and these complexes activate Ras guanine nucleotide exchange factors (GEFs; Figure 1). 10 GEFs catalyze dissociation of guanine nucleotides from Ras, which is followed by ...

show abstract

Development of Highly Potent Inhibitors of the Ras‐Targeting Human Acyl Protein Thioesterases Based on Substrate Similarity Design

Cited by 21 publications

References 34 publications

Characterization of a Serine Hydrolase Targeted by Acyl-protein Thioesterase Inhibitors in Toxoplasma gondii

Characterization of a Serine Hydrolase Targeted by Acyl-protein Thioesterase Inhibitors in Toxoplasma gondii

Identification of Acyl Protein Thioesterases 1 and 2 as the Cellular Targets of the Ras‐Signaling Modulators Palmostatin B and M

Targeting oncogenic Ras signaling in hematologic malignancies

Contact Info

Product

Resources

About