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PD 0332991 – THE POTENT CDK INHIBITOR

by Selleckchem | Mar 19 2012

PD 0332991 PROPERTIES:

One of the most important functions any cell can do is the reproduction of itself, identical down to the finest degree. The process that achieves the basic necessity of life itself is called the cell cycle and is a highly controlled / regulated process. This process is divided into two stages; the first is the interphase stage which has four distinct phases [1-5]. The second stage is the cell division stage and this consists solely of the cell mitosis. Starting at stage 1 the cell is usually at rest or in a condition where no replication is occurring, this is referred to as the G₀ phase. When a cell receives an external trigger to divide the cell moves into the G1 phase, here the cell will accumulated nutrients and molecules necessary for the construction of all the components of a new cell. Cells use this material to increase in size to accommodate the new material and to generate sufficient cell membrane so a division can occur. The G1 phase has control mechanisms to recognize the successful completion of all necessary components of this phase [6-8]. Once the signal is given that all specifications have been met the cell movers into the S phase. In the S phase the DNA is duplicated using the collected raw materials, proteins specifically designed for the purpose of checking al the molecules created are corrects transmit signals for the cell to enter the G2 phase. This is the last phase prior to mitosis and all the preparatory work is verified by control proteins, once everything is verified the signal is sent to initiate the M phase and mitosis begins [9].

The control proteins Cyclin and cyclin dependant kinases (CDK) is one of the mechanisms used by nature to control the cell cycle process. Cyclin forms a heterodimer with the CDK to activate its phosphorylation which in turn triggers either progression in the cell cycle or termination of the process [10]. There are 11 known cyclin’s and at least 9 CDK’s in mammalian cells so the combinations possible are quite large although some degree of conformity is present [1]. The formation the dimer was considered to be a prime target for chemotherapy where uncontrolled cell division is the controlling factor in tumor growth [11]. Inhibitors designed specifically to target the CDK4/6 – cyclin D pathway are being tested clinically, aberration in this pathway almost universal in tumor growth hence a very broad range of possibilities were envisaged [12]. The PD 0332991 CDK inhibitor is one of several compounds reaching the clinical testing phase.

PD-0332991: Properties and Availability

Based on a combination of purine and pyrimidine as a secondary amine the PD-0332991 structure lends itself to oral formulation [13]. With potent activity against CDK 4&6 (IC50 11& 16 nM respectively) this molecule is available for research purposes from numerous PD-0332991 suppliers [14]. PD-0332991 is supplied predominantly as the HCl salt and while for cell culture work the PD-0332991 solubility in DMSO is adequate, it is also soluble in aqueous buffers. To buy PD-0332991 the range in PD-0332991 price can be large (50mg, $570-$936). Not much is reported on PD-0332991 stability although most suppliers standardize to storage at -20°C for maximum of 2 years.

PD0332991 Preclinical testing and Clinical status

Initial preclinical work quickly established that PD0332991 was a specific inhibitor for CDK4 and 6 with little or no activity for many other key tyrosine kinases. This was atypical at this stage for the development of CDK inhibitors since previously all focus had been on the CDK 1 & 2 inhibition [15]. The potency of PD0332991 towards its targets was such that the in vivo testing for anti tumor activity was initiated at the earliest opportunity. Demonstrated to cause G1 arrest in myeloma cells PD0332991 was tested in xenografts models where it shown significant anti-tumor activity [16;17]. PD0332991 quickly established itself as a potential therapy for breast cancers, include the ER+ and HER2 mutated cell lines [18;19]. In addition PD032991 demonstrate significant abilities to suppress hepatocyte proliferation even in the RB mutated cell lines, indicating a potential role in liver cancer and glioblastoma as well [20;21].

PD 0332991 clinical trials were initiated in 2010 and are near completion but a single phase 1 study has been reported. Conducted in patients with retinoblastoma protein positive conditions for which therapy had demonstrated potential PD0332991 demonstrated 30% stable disease and one testicular cancer exhibited a partial response. This significant result confirms PD032991’s potential and the results of the current clinical trials in breast

References

1. Owa T, Yoshino H et al. Cell cycle regulation in the G1 phase: a promising target for the development of new chemotherapeutic anticancer agents. Curr Med Chem 2001; 8(12):1487-1503.

2. Karunagaran D, Joseph J et al. Cell growth regulation. Adv Exp Med Biol 2007; 595:245-268.

3. Hall PA. Cell proliferation. J Pathol 1991; 165(4):349-354.

4. Guo M, Hay BA. Cell proliferation and apoptosis. Curr Opin Cell Biol 1999; 11(6):745-752.

5. Golias CH, Charalabopoulos A et al. Cell proliferation and cell cycle control: a mini review. Int J Clin Pract 2004; 58(12):1134-1141.

6. Murray A. Cell cycle checkpoints. Curr Opin Cell Biol 1994; 6(6):872-876.

7. Eastman A. Cell cycle checkpoints and their impact on anticancer therapeutic strategies. J Cell Biochem 2004; 91(2):223-231.

8. Tannoch VJ, Hinds PW et al. Cell cycle control. Adv Exp Med Biol 2000; 465:127-140.

9. Gorbsky GJ. Cell cycle checkpoints: arresting progress in mitosis. Bioessays 1997; 19(3):193-197.

10. Kamb A. Cell-cycle regulators and cancer. Trends Genet 1995; 11(4):136-140.

11. Ganchevska PG, Sarafian VS. Cell cycle--molecular mechanisms and therapeutic perspectives in oncology. Folia Med (Plovdiv ) 2004; 46(1):9-14.

12. Collins I, Garrett MD. Targeting the cell division cycle in cancer: CDK and cell cycle checkpoint kinase inhibitors. Curr Opin Pharmacol 2005; 5(4):366-373.

13. Lu H, Schulze-Gahmen U. Toward understanding the structural basis of cyclin-dependent kinase 6 specific inhibition. J Med Chem 2006; 49(13):3826-3831.

14. Baughn LB, Di LM et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 2006; 66(15):7661-7667.

15. Toogood PL, Harvey PJ et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005; 48(7):2388-2406.

16. Menu E, Garcia J et al. A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Res 2008; 68(14):5519-5523.

17. Michaud K, Solomon DA et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 2010; 70(8):3228-3238.

18. Finn RS, Dering J et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009; 11(5):R77.

19. Sutherland RL, Musgrove EA. CDK inhibitors as potential breast cancer therapeutics: new evidence for enhanced efficacy in ER+ disease. Breast Cancer Res 2009; 11(6):112.

20. Rivadeneira DB, Mayhew CN et al. Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology 2010; 138(5):1920-1930.

21. Wiedemeyer WR, Dunn IF et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc Natl Acad Sci U S A 2010; 107(25):11501-11506.