BackgroundHec1 (NDC80) is an integral part of the kinetochore and is overexpressed in a variety of human cancers, making it an attractive molecular target for the design of novel anticancer therapeutics. A highly potent first-in-class compound targeting Hec1, TAI-1, was identified and is characterized in this study to determine its potential as an anticancer agent for clinical utility.MethodsThe in vitro potency, cancer cell specificity, synergy activity, and markers for response of TAI-1 were evaluated with cell lines. Mechanism of action was confirmed with western blotting and immunofluorescent staining. The in vivo potency of TAI-1 was evaluated in three xenograft models in mice. Preliminary toxicity was evaluated in mice. Specificity to the target was tested with a kinase panel. Cardiac safety was evaluated with hERG assay. Clinical correlation was performed with human gene database.ResultsTAI-1 showed strong potency across a broad spectrum of tumor cells. TAI-1 disrupted Hec1-Nek2 protein interaction, led to Nek2 degradation, induced significant chromosomal misalignment in metaphase, and induced apoptotic cell death. TAI-1 was effective orally in in vivo animal models of triple negative breast cancer, colon cancer and liver cancer. Preliminary toxicity shows no effect on the body weights, organ weights, and blood indices at efficacious doses. TAI-1 shows high specificity to cancer cells and to target and had no effect on the cardiac channel hERG. TAI-1 is synergistic with doxorubicin, topotecan and paclitaxel in leukemia, breast and liver cancer cells. Sensitivity to TAI-1 was associated with the status of RB and P53 gene. Knockdown of RB and P53 in cancer cells increased sensitivity to TAI-1. Hec1-overexpressing molecular subtypes of human lung cancer were identified.ConclusionsThe excellent potency, safety and synergistic profiles of this potent first-in-class Hec1-targeted small molecule TAI-1 show its potential for clinically utility in anti-cancer treatment regimens.

Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers.

Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI 50 ¼ 14.29-73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI 50 > 10 mmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers.

Globo H antigen is a hexasaccharide originally isolated as a ceramide-linked glycolipid from the human breast cancer cell line MCF-7. Globo H is also highly expressed in many other cancers such as colon cancer, ovarian cancer, gastric cancer, pancreatic cancer, lung cancer, and prostate cancer. DCBD16001 is an ADC from humanized anti-Globo H antibody DCBPR1101. DCBPR1101 and DCBD16001 both show good binding affinities against Globo H antigen. DCBD16001 also shows high cytotoxicity in Globo H overexpressing cell line MCF-7 and HCC-1428 and shows no cytotoxicity in Globo H negative cell line BT-474. DCBD16001 can internalize to target cell more than 50% within 4.0 hours. In vivo evaluation data indicates that DCBD16001 shows acceptable PK profiles and good efficacy. It shows nearly 80% tumor growth inhibition in HCC-1428 xenograft model. DCBD16001 is a candidate under pre-clinical development and expected to apply IND submission within two years. Citation Format: Wei-Ting Sun, Shih-Hsien Chuang, Chao-Pin Lee, Yi-Jen Chen, Win-Yin Wei, Ying-Shuan Lee, Chuan-Lung Hsu, Yu-Chin Nieh, Chia-Cheng Wu. Development of anti-Globo H ADC against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 813.

A series of 3-O-acylated (−)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared by the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (−)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids using DCC and DMAP and then desilylated with aqueous HF to provide the corresponding products. For 3-O-acylated (−)-epigallocatechins with saturated fatty acids, the 5α-reductase inhibitory activity increased with the increasing numbers of carbon atoms at the C3-O position, reaching maximum for 16 carbon atoms (compound 4h, with palmitic acid) with an IC50 of 0.53 µM, which was ∼12-fold more potent than EGCG (IC50 = 6.29 M). Introduction of monounsaturated fatty acid to the C3-O position of (−)-epigallocatechins enhanced the activity, providing the most potent compound 6 (IC50 = 0.48 µM, with palmitoleic acid), which showed moderate anti-tumor activity in a PC-3 prostate cancer xenograft model. Replacement of the ester moiety at C3-O with carbamate, or permethylation or peracylation of hydroxyl groups diminished 5α-reductase inhibitory activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A89.

<div>Abstract<p>Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI₅₀ = 14.29–73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI₅₀ > 10 μmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of <i>in vivo</i> tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers. <i>Mol Cancer Ther; 13(6); 1419–30. ©2014 AACR</i>.</p></div>

<p>PDF - 1333K, Figure S1. Summary of structural modifications. Figure S2. Hec1 localization. Figure S3. Activation of apoptosis. Figure S4. Subacute toxicity study: histological sections. Figure S5. Subacute toxicity study: organ weight and blood indices. Figure S6. Additional breast cancer xenograft mouse models.</p>

<p>PDF - 1333K, Figure S1. Summary of structural modifications. Figure S2. Hec1 localization. Figure S3. Activation of apoptosis. Figure S4. Subacute toxicity study: histological sections. Figure S5. Subacute toxicity study: organ weight and blood indices. Figure S6. Additional breast cancer xenograft mouse models.</p>