Targeting carbonic anhydrase IX with small organic ligands

Wichert, Moreno; Krall, Nikolaus

doi:10.1016/j.cbpa.2015.02.005

Cited by 29 publications

(37 citation statements)

References 47 publications

(57 reference statements)

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“…The potent therapeutic activity observed with compounds 4a and 5a suggests that these products may provide a benefit to patients with kidney cancer, as the majority of clear cell renal cell carcinomas are strongly positive for this target [32][33][34]. The biodistribution profiles of acetazolamide derivatives compares favourably with the ones previously reported for other ligands [23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

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Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Cazzamalli

Corso

Neri

2016

Molecular Cancer Therapeutics

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In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/Kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/Kg, with a tumor:blood ratio of 80:1 at 6 h. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, while drug derivatives devoid of the acetazolamide moiety did not exhibit any detectable anticancer activity at the same doses. The observation of tumor regression with a noninternalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX.

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Section: Discussionmentioning

confidence: 99%

“…CAIX is a membrane protein, expressed in the majority of clear cell renal cell carcinomas [32][33][34]. CAIX is virtually undetectable in most normal adult tissues, except for certain structures in the gastrointestinal tract (stomach, duodenum, gallbladder), which are strongly positive for the antigen.…”

Section: Introductionmentioning

confidence: 99%

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Cazzamalli

Corso

Neri

2016

Molecular Cancer Therapeutics

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“…The quaternary methyl ammonium (QMA) anion exchange and C18 light Sep-Pak cartridges (1 cm 3 , 50 mg) were obtained from Waters (Milford, MA). Purification and quality control of 18 F-labeled 2 were performed on an Agilent (Santa Clara, CA) HPLC system equipped with a model 1200 quaternary pump, a model 1200 UV absorbance detector, and a Bioscan (Washington, DC) NaI scintillation detector. The radio-detector was connected to a Bioscan B-FC-1000 Flow-count system, and the output from the Bioscan Flow-count system was fed into an Agilent 35900E Interface, which converted the analog signal to digital signal.…”

Section: Chemicals and Instrumentationmentioning

confidence: 99%

“…The HPLC columns used were a semi-preparative column (Phenomenex C18, 5 l, 250 Â 10 mm) and an analytical column (Phenomenex C18, 5 l, 250 Â 4.6 mm). 18 F-Fluoride was produced by the 18 O(p, n) 18 F reaction using an Advanced Cyclotron Systems Inc. (Richmond, BC, Canada) TR19 cyclotron. Radioactivity of 18 F-labeled 2 was measured using a Capintec (Ramsey, NJ) CRC V R -25 R/W dose calibrator, and the radioactivity of mouse tissues collected from biodistribution studies were counted using using a Perkin Elmer (Waltham, MA) Wizard2 2480 automatic gamma counter.…”

Section: Chemicals and Instrumentationmentioning

confidence: 99%

“…In preclinical studies, attenuation of CA-IX activity by small molecule inhibitors has been shown to be efficacious in reducing primary tumor growth and distant metastases [12][13][14][15] . CA-IX inhibitors have also been used as delivery vectors of cytotoxic payloads to target tumor cells within hypoxic niches [16][17][18] . Complementing these therapeutic efforts has been the development of CA-IX radiotracers derived from inhibitors for positron emission tomography (PET) and single photon emission computed tomography (SPECT) applications [19][20][21][22][23][24][25][26][27][28][29][30][31] .…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis and evaluation of¹⁸F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

Zhang

Lau

Zhang

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Carbonic anhydrase IX (CA-IX) is a marker for tumor hypoxia, and its expression is negatively correlated with patient survival. CA-IX represents a potential target for eliminating hypoxic cancers. We synthesized fluorinated cationic sulfonamide inhibitors 1-3 designed to target CA-IX. The binding affinity for CA-IX ranged from 0.22 to 0.96 lM. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with 18 F in 10 ± 4% decay-corrected radiochemical yield with 85.1 ± 70.3 GBq/lmol specific activity and >98% radiochemical purity.18 F-labeled 2 was stable in mouse plasma at 37 C after 1 h incubation. PET/CT imaging was conducted at 1 h post-injection in a human colorectal cancer xenograft model.18 F-labeled 2 cleared through hepatobiliary and renal pathways. Tumor uptake was approximately 0.41 ± 0.06% ID/g, with a tumor-to-muscle ratio of 1.99 ± 0.25. Subsequently, tumor xenografts were visualized with moderate contrast. This study demonstrates the use of a cationic motif for conferring isoform selectively for CA-IX imaging agents. ARTICLE HISTORY

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Hit‐Validation Methodologies for Ligands Isolated from DNA‐Encoded Chemical Libraries

Zimmermann

Rieder

et al. 2017

ChemBioChem

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DNA-encoded chemical libraries (DECLs) are large collections of compounds linked to DNA fragments, serving as amplifiable barcodes, which can be screened on target proteins of interest. In typical DECL selections, preferential binders are identified by high-throughput DNA sequencing, by comparing their frequency before and after the affinity capture step. Hits identified in this procedure need to be confirmed, by resynthesis and by performing affinity measurements. In this article we present new methods based on hybridization of oligonucleotide conjugates with fluorescently labeled complementary oligonucleotides; these facilitate the determination of affinity constants and kinetic dissociation constants. The experimental procedures were demonstrated with acetazolamide, a binder to carbonic anhydrase IX with a dissociation constant in the nanomolar range. The detection of binding events was compatible not only with fluorescence polarization methodologies, but also with Alphascreen technology and with microscale thermophoresis.

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Targeting carbonic anhydrase IX with small organic ligands

Cited by 29 publications

References 47 publications

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Design, synthesis and evaluation of¹⁸F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

Hit‐Validation Methodologies for Ligands Isolated from DNA‐Encoded Chemical Libraries

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Targeting carbonic anhydrase IX with small organic ligands

Cited by 29 publications

References 47 publications

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

Design, synthesis and evaluation of18F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

Hit‐Validation Methodologies for Ligands Isolated from DNA‐Encoded Chemical Libraries

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Design, synthesis and evaluation of¹⁸F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging