CUDC -101: HDAC inhibitor

Introduction: HDAC inhibition

Regulation of the activity of the proteins that initiate and transmitted signals for the cellular growth or gene transcription is a vital process in the mammalian system. There are many different mechanisms that perform this task but o of the more significant is the addition or removal of an acetyl group. The enzyme’s most responsible for this activity is known as “Histone deacetylase” and “Histone transferase” or more commonly known as HDAC and HAT respectively [1;2]. In a normal situation these two enzymes operate in a balanced mechanism but genetic aberrations can significantly affect this balance in one way or another. Most typically it is observed that the HDAC is over expressed or in a permanent “on” condition in most diseased states.  With over 18 currently known isoforms of HDAC divided into class’s based on the mechanism of action this represents a major target for chemotherapeutic action [3-6] To target HDAC an inhibitor should be able to interfere with the ligand – enzyme binding which occurs in the tyrosine kinase domain and two classes out of 4 HDAC’s  require Zinc to catalyse the reaction [6]. The other two classes do not require zinc but are dependant of NAD+ for their function.

Inhibition of HDAC´s tends to be global with most of the current treatments inhibiting both class 1 and class II categories. This pan-inhibition theoretically would inhibit most of the gene transcription and proliferation functions of the cell, systemically this could viewed as a negative idea since the likelihood of the host dying is very large. However, preclinical work demonstrated that this is not the case in a variety of cell lines. CUDC-101 HDAC inhibitor  is a derivative of a quinazoline compound and has demonstrated antitumor activity a variety of cell lines including lung, breast, pancreatic, head/neck and colon. The unique aspect of CUDC101 is its ability to inhibit HDAC (class 1&2), EGFR and HIR2.

CUDC-101: Properties and Availability

The CUDC-101 EGFR inhibitor is a relatively new molecule and under development by Curtis Inc since 2008. The CUDC-101 structure was designed by considering the 3-dimensional space of the binding domain of the HDAC protein and the EGFR/HER2 inhibition templates. Utilizing hydroxamic acid as the Zinc interaction component a link was made to an EGFR/HER2 inhibition model. By adapting the structure slightly a series of quinazoline compounds was formulated. Testing this series against HDAC, EGFR and HER2 the CUDC-101 IC50’s indicated that CUDC-101 HER2 inhibitor was a potent inhibitor of all three (4., 2.4 & 15.7 nM respectively). CUDC-101 solubility in water and ethanol has not been reported, however CUDC-101 is reported as being soluble in DMSO with exact details being given. For the solid form of CUDC-101 stability is not an issue since it can be stored at -20°C with an expiration date of 2 years. The individual can buy CUDC-101 at a competative CUDC-101 price from a range of of CUDC-101 suppliers. Although a 10 mg vial can range from $87 up to $320 when compared between suppliers.

 CUDC-101: Preclinical and clinical activity

CUDC-101 activity was determined against a panel of cell lines along side its potential main competitors (Erlotinib, Lapatinib, SAHA & combinations of SAHA with Erlotinib/Lapatinib). Results indicated that in NSCLC CUDC-101 is 3 – 9 fold more potent that Erlotinib or Erlotinib + SAHA.  A similar result was seen in the panels of both pancreatic and prostate cell lines. In renal, breast, colon and liver the comparison with Erlotinib / Combination was seen to be upwards of 20 fold high in potency, slightly lower (10 fold) but similar results with a comparison to a lapatinib – SAHA combination.[7;8].

CUDC-101 clinical trial are currently running for two phase 1 and one phase 1b studies into patinets with a) solid tumors, b) in combination with cisplatin in head & neck (papillomavris negative) and a study into the safety / toxicity / pharmacokinetics in solid tumors (HNC; NSCLC; Gastric Cancer, Breast Cancer and Liver Cancer). The initial reports from the phase 1 trial, is that CUDC-101 has demonstrated antitumor activity in breast and head & neck cancers.



    1.    Codd R, Braich N et al. Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. Int J Biochem Cell Biol 2009; 41(4):736-739.

    2.    Rajendran P, Williams DE et al. Metabolism as a key to histone deacetylase inhibition. Crit Rev Biochem Mol Biol 2011; 46(3):181-199.

    3.    Martin M, Kettmann R et al. Class IIa histone deacetylases: regulating the regulators. Oncogene 2007; 26(37):5450-5467.

    4.    Witt O, Deubzer HE et al. HDAC family: What are the cancer relevant targets? Cancer Lett 2009; 277(1):8-21.

    5.    Brunmeir R, Lagger S et al. Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation. Int J Dev Biol 2009; 53(2-3):275-289.

    6.    Jurkin J, Zupkovitz G et al. Distinct and redundant functions of histone deacetylases HDAC1 and HDAC2 in proliferation and tumorigenesis. Cell Cycle 2011; 10(3):406-412.

    7.    Lai CJ, Bao R et al. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res 2010; 70(9):3647-3656.

    8.    Cai X, Zhai HX et al. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanam ide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem 2010; 53(5):2000-2009.

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Cat.No. Product Name Information Publications Customer Product Validation
S1194 CUDC-101 CUDC-101 is a potent multi-targeted inhibitor against HDAC, EGFR and HER2 with IC50 of 4.4 nM, 2.4 nM, and 15.7 nM, and inhibits class I/II HDACs, but not class III, Sir-type HDACs. Phase 1. (17) (3)

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