CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy

Bao, Rong; Lai, Cheng-Jung; Qü, Hui; Wang, Da-Gong; Yin, Ling; Zifcak, Brian; Atoyan, Ruzanna; Wang, Jing; Samson, Maria; Forrester, Jeffrey; DellaRocca, Steven; Xu, Guang-Xin; Tao, Xu; Zhai, Hai-Xiao; Cai, Xiong; Qian, Changgeng

doi:10.1158/1078-0432.ccr-09-0152

Cited by 103 publications

(101 citation statements)

References 43 publications

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“…However, clearance of NVP-BEP800 from all tissues was much more rapid than tumor with half-life of 1.6 to 3 hours, and no hepatotoxicity was observed in the preclinical toxicology studies (data not shown). The phenomenon of high liver exposure has also been observed with CUDC-305 (35), but in comparison with NVP-BEP800, CUDC-305 had a long liver retention time resulting in a reduced tumor to liver half-life ratio. NVP-BEP800 exhibited no appreciable brain penetrance, suggesting that central nervous system toxicities should not be an issue for this molecule.…”

Section: Discussionmentioning

confidence: 85%

“…In binding assays, NVP-BEP800 bound competitively with a resorcinol-based fluorescent probe to the ATPase site of Hsp90, with an IC 50 of 58 nmol/L. This was less potent than NVP-AUY922 (33) but comparable with other oral Hsp90 inhibitors such as BIIB021 and CUDC-305 (35,36). NVP-BEP800 showed selectivity versus the related GHKL ATPases Grp94 and Trap-1 of >70-fold.…”

Section: Discussionmentioning

confidence: 91%

“…CUDC-305 and BIIB021 exhibit similar affinity for Hsp90 and inhibit tumor cell growth to an equivalent extent as NVP-BEP800. They are highly orally bioavailable (35,36) yet require significantly higher doses of compound to inhibit tumor growth to the same extent as NVP-BEP800. For example, 30 mg/kg daily dosing of NVP-BEP800 induces tumor regression in BT-474 xenograft models, whereas 120 mg/kg daily BIIB021 and 160 mg/kg twice daily CUDC-305 are required to induce similar tumor responses.…”

Section: Discussionmentioning

confidence: 99%

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Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800

Massey

Schoepfer

Brough

et al. 2010

Molecular Cancer Therapeutics

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Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules involved in cell proliferation, survival, and transformation. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerable interest as a therapeutic target. NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor that binds to the NH 2 -terminal ATP-binding pocket of Hsp90. NVP-BEP800 showed activity against a panel of human tumor cell lines and primary human xenografts in vitro at nanomolar concentrations. In A375 melanoma and BT-474 breast cancer cell lines, NVP-BEP800 induced client protein degradation (including ErbB2, B-Raf V600E , Raf-1, and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well tolerated and induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. In these tumor models, NVP-BEP800 modulated Hsp90 client proteins and downstream signaling pathways at doses causing antitumor activity. NVP-BEP800 showed in vivo activity in a variety of dosing regimens covering daily to weekly schedules, potentially providing a high degree of flexibility in dose and schedule within the clinical setting. Overall, given the mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, NVP-BEP800 is an exciting new oral Hsp90 inhibitor warranting further development.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800

Massey

Schoepfer

Brough

et al. 2010

Molecular Cancer Therapeutics

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“…Inhibitor accumulation in tumors, coupled with rapid clearance from blood and normal tissue, has been observed for multiple classes of HSP90 inhibitors and may be due in part to the kinetics of the inhibitor binding to tumor-derived HSP90 complexes. (19)(20)(21)(22)(23) The potential advantage of compounds binding to HSP90 for a longer duration has been illustrated previously by comparing the monomeric ansamycin inhibitor 17-AAG with a dimeric variant that exhibited slow off-rate kinetics. (18,24) Several structurally distinct HSP90 inhibitors are progressing through clinical development with early indications of clinical responses in published phase I and II data.…”

mentioning

confidence: 87%

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

Graham¹,

Curry²,

Smyth³

et al. 2012

Cancer Science

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A ubiquitously expressed chaperone, heat shock protein 90 (HSP90) is of considerable interest as an oncology target because tumor cells and oncogenic proteins are acutely dependent on its activity. AT13387 (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, L-lactic acid salt) a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. This inhibitor has induced the degradation of specific HSP90 client proteins for up to 7 days in tumor cell lines in vitro. The primary driver of cell growth (mutant epidermal growth factor receptors) was particularly sensitive to HSP90 inhibition. The long duration of client protein knockdown and suppression of phospho-signaling seen in vitro after treatment with AT13387 was also apparent in vivo, with client proteins and phospho-signaling suppressed for up to 72 h in xenograft tumors after treatment with a single dose of AT13387. Pharmacokinetic analyses indicated that while AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. AT13387's long duration of action enabled, in particular, its efficacious once weekly administration in human lung carcinoma xenografts. The use of longer-acting HSP90 inhibitors, such as AT13387, on less frequent dosing regimens has the potential to maintain antitumor efficacy as well as minimize systemic exposure and unwanted effects on normal tissues. (Cancer Sci 2012; 103: 522-527) T he super-chaperone system is involved in the folding and maturation of newly synthesized proteins.(1,2) HSP90 in particular aids in the folding and maturation of a distinct subset of proteins, which includes kinases, cell surface receptors and transcription factors. (3,4) The N-terminal domain ATPase activity of HSP90 is essential for this function.(5) Inhibition of this domain induces remodeling of the HSP90 chaperone complex, resulting in the recruitment of ubiquitin ligases, polyubiquitination and subsequent proteasomal degradation of HSP90 client proteins.(6,7) Through this mechanism, the inhibition of a single target enzyme can have a wide effect on the stability and, hence, the function of a large set of client proteins. As many oncogenic proteins are HSP90 clients, HSP90 inhibition has been found to have broad antitumor effects.(8-10) In contrast to more recent targeted therapies, where the appearance of new driver mutations or resistance mutations result in a loss of efficacy, client protein mutation increases dependence on HSP90 chaperoning activity as these mutations tend to render the proteins less stable. (11)(12)(13) Previous studies have also demonstrated that the constitutively activated mutant forms of EGFR are particularly dependent on HSP90 both in vitro and in vivo, (14)(15)(16) indicating an HSP90 inhibitor may be particularly efficacious in mutant EGFR tumors.After HSP90 inhibiti...

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“…We applied these fundamentals to establish a new drug delivery system termed HSP90 inhibitor-drug conjugates, or HDC, based on the property that small-molecule inhibitors of HSP90 are preferentially retained in tumor cells in contrast to their rapid clearance from the circulation and normal tissues (8)(9)(10)(11)(12). HSP90 is a highly conserved molecular chaperone that plays an indispensable role in regulating the maturation and functional stability of a vast repertoire of cellular client proteins (13).…”

Section: Introductionmentioning

confidence: 99%

HSP90 Inhibitor–SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors

Proia

Smith

Zhang

et al. 2015

Molecular Cancer Therapeutics

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The clinical benefits of chemotherapy are commonly offset by insufficient drug exposures, narrow safety margins, and/or systemic toxicities. Over recent decades, a number of conjugate-based targeting approaches designed to overcome these limitations have been explored. Here, we report on an innovative strategy that utilizes HSP90 inhibitor-drug conjugates (HDC) for directed tumor targeting of chemotherapeutic agents. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to SN-38, the active metabolite of irinotecan. Mechanistic analyses in vitro established that high-affinity HSP90 binding conferred by the inhibitor backbone could be exploited for conjugate accumulation within tumor cells. In vivo modeling showed that the HSP90 inhibitor moiety was required for selective retention of STA-12-8666, and this enrichment promoted extended release of active SN-38 within the tumor compartment. Indeed, controlled intratumoral payload release by STA-12-8666 contributed to a broad therapeutic window, sustained biomarker activity, and remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. Overall, STA-12-8666 has been developed as a unique HDC agent that employs a distinct mechanism of targeted drug delivery to achieve potent and sustained antitumor effects. These findings identify STA-12-8666 as a promising new candidate for evaluation as novel anticancer therapeutic.

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CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy

Cited by 103 publications

References 43 publications

Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800

Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

HSP90 Inhibitor–SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors

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