AZD1152 – AN AURORA KINASE INHIBITOR

by Selleckchem | Mar 13 2012

Inhibition of AURORA KINASES in relation to cancer:

Mitosis is a key process in the regeneration of cellular material and two key regulators of this function are serine and threonine kinases which are more commonly known as Aurora Kinases. Three isoforms of the aurora kinase have been isolated in human tissue (A,B and C) which function on different aspects of the mitosis cycle. Aurora kinases are significant as targets for chemotherapeutic action since they are elevated in many different cancer types.[1;2] Small molecule inhibitors of aurora kinases, such as VX-680 [3] (Tozasertib), ZM447439 [4] and Hesperadin [5], have been developed and successfully trialed on several cancer groups including breast [6], colon [7], prostate [8] and in acute myeloid leukemia (AML) [9-11].

Barasertib (AZD1152-HQPA) Chemical Structure

AZD1152 - A novel Aurora kinase inhibitor

AZD1152 Aurora inhibitor is a novel small molecule prodrug that specifically targets the Aurora kinases. Currently marketed under the trade name Barasertib by AstraZeneca, it specifically targets the Aurora B (IC50 – 0.37nM) kinase compared to Aurora A (IC50 – 1368 nM. AZD1152 prodrug is converted systemically to AZD1152- hydroxy pyrazole – aminoquinazoline or AZD1152-HQPA, which is the active form of the compound [12;13].

AZD1152 - Preclinical investigations

Preclinical work demonstrated that AZF1152-HQPA caused a sequence of events in tumor xenographs leading to cellular apoptosis [14]. Initially AZF1152-HQPA cause a temporary inhibition of the phosphorylation of histone H3. This caused an accumulation of 4N DNA in the cell which lead to elevated numbers of polyploidy cells, this was significant compared to control and was evident in the increase in apoptosis observed histologically. Tumor xenographs investigated included lung, hematopoietic and colon samples. AZF1152-HQPA was investigated in conjunction with leukemia cell line and was to inhibit HL-60, NB4&MOLM13 (acute myeloid leukemia, AML); PALL-2 (acute lymphoblastic leukemia, ALL); EOL-1 (acute eosinophillic leukemia, K562 (chronic myeloid leukemia) and MV4-11 (biphenotypic leukemia) [9]. More significantly AZD1152 demonstrate synergistic effects in combinations with more traditional forms of chemotherapy such vincristine, daunorubicin, CPT-11 [15], oxaliplatin and gemcitabine [16]. Also significant was the observation that AZF1152-HQPA enhance the radio-sensitivity of prostate cancer cells. [17]. These indications of significant clinical benefits have lead to several phase I and phase 11 clinical trials being under taken globally.

AZD1152 - Clinical status

AZD1152 is marketed under the trade name Barasertib and is being tested in several phase 1 studies. The maximum tolerated dose (MTD) was established to be 1200 mg which demonstrated a 25% tumor response rate in AML patients. [11] Lower doses of 400 -650 mg gave less toxicological side effects but no response was observed in tumor reduction, although a 15% rate of stable disease was determined [18]. In Japanese AML patients a 19% hematological response rate was observed at the 1200 mg MTD. No difference in pharamcokinetics for AZD1152 clinical trial was observed between Asian and Caucasian subjects. [19]

AZD1152 – Market availability

You can Buy AZD1152 online and is available from several suppliers as both the prodrug and as the hydroxylated active component. AZD1152 price ranges from $150 – 200 for a 5 mg vial depending on the AZD1152 supplier. AZD1152 solubility in DMSO is good. AZD1152 stability in solution is good and can be stored -20^oC for a minimum of 2 years.

References

1. Agnese V, Bazan V et al. The role of Aurora-A inhibitors in cancer therapy. Ann Oncol 2007; 18 Suppl 6:vi47-vi52.

2. Doggrell SA. Dawn of Aurora kinase inhibitors as anticancer drugs. Expert Opin Investig Drugs 2004; 13(9):1199-1201.

3. Lavelle F. [The Aurora kinase inhibitor VX680, leader of a new family of antitumoral agents]. Bull Cancer 2004; 91(4):300-301.

4. Georgieva I, Koychev D et al. ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio- and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines. Neuroendocrinology 2010; 91(2):121-130.

5. Hauf S, Cole RW et al. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol 2003; 161(2):281-294.

6. Yang H, Ou CC et al. Aurora-A kinase regulates telomerase activity through c-Myc in human ovarian and breast epithelial cells. Cancer Res 2004; 64(2):463-467.

7. Azzariti A, Bocci G et al. Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer. Br J Cancer 2011; 104(5):769-780.

8. Lee EC, Frolov A et al. Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 2006; 66(10):4996-5002.

9. Yang J, Ikezoe T et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 2007; 110(6):2034-2040.

10. Walsby E, Walsh V et al. Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts. Haematologica 2008; 93(5):662-669.

11. Lowenberg B, Muus P et al. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia. Blood 2011; 118(23):6030-6036.

12. Tao Y, Leteur C et al. The aurora B kinase inhibitor AZD1152 sensitizes cancer cells to fractionated irradiation and induces mitotic catastrophe. Cell Cycle 2009; 8(19):3172-3181.

13. Aihara A, Tanaka S et al. The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma. J Hepatol 2010; 52(1):63-71.

14. Wilkinson RW, Odedra R et al. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 2007; 13(12):3682-3688.

15. Nair JS, de SE et al. The topoisomerase I poison CPT-11 enhances the effect of the aurora B kinase inhibitor AZD1152 both in vitro and in vivo. Clin Cancer Res 2009; 15(6):2022-2030.

16. Azzariti A, Bocci G et al. Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer. Br J Cancer 2011; 104(5):769-780.

17. Niermann KJ, Moretti L et al. Enhanced radiosensitivity of androgen-resistant prostate cancer: AZD1152-mediated Aurora kinase B inhibition. Radiat Res 2011; 175(4):444-451.

18. Phase I and pharmacological study of the novel aurora kinase inhibitor AZD1152. 2006.

19. Tsuboi K, Yokozawa T et al. A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia. Leuk Res 2011; 35(10):1384-1389.