PD0325901 – SUCCESS OF A MEK INHIBITOR

by Selleckchem | Mar 19 2012

Introduction: MEK inhibition

In numerous tumors investigates for kinase activity one of the key pathways to stand out is the RAS / RAF pathway. With mutations of both RAS (KRAS) and RAF (BRaf^V600E) demonstrating significant resistance in chemotherapeutic action for EGFR, RAS and RAF inhibitors [1], a target further down the signaling pathway was thought to be a possible side step to this resistance. EGFR is a transmembrane protein which passes a signal (via phosphorylation) to an internal membrane bound protein (GRBS and SOS) [2]. This signal is passed down stream via RAS and RAF to a nexus point, MEK. This protein is the target of several pathway crossovers and while MEK itself has not been shown to be mutated; it is recipient of signals from several proteins that are. Signaling via MEK can lead to several different functions in the cell include cell growth, proliferation and migration [3].

The PD0325901 MEK inhibitor is similar in its mechanism of action to the majority of the tyrosine kinase inhibitors by irreversibly binding to the ATP binding domain preventing target protein phosphorylation [4].

PD0325901: Properties and availability

Developed by Pfizer after the initial trials with CI-1040 proved to be ineffective, due to poor solubility and high clearance rates, the molecule PD0325901 has demonstrated specificity towards MEK 1 & 2 [5]. PD0325901 solubility in DMSO is greater than CI-1040 achieving a 12 mg/ml solution as well as a 6.3 mg/ml solution in ethanol. The PD0325901 structure is based on the difluoro benzamide structure of CI-1040 with alterations to the phenylamino side chain (replacement of Cl with F) and to the methoxy side chain on the benzamide core (replacement with propoxy group). The adjustments to the structure preserved its inhibitory abilities yet solubility increase and an improved pharmacokinetic profile. When stored at -20°C PD0325901 stability is given as 2 years before retesting is required. Pd0325901 suppliers vary siginificantly in the PD0325901 price of a 5 mg vial but researchers can buy PD032901 for between $55 -$453

PD0325901: Preclinical testing

In murine models of prostate cancer the molecule PD0325901 in combinations with an inhibitor of mTOR (a similar nexus protein) significant in vitro anti-tumor activity was observed [5]. In thyroid cancer the BRaf mutation is a common occurance and resistance to inhibitors of EGFR or BRaf is often seen. Inhibition with MEK inhibitor PD0325901 circumvents this mutational resistance and demonstrates significant anti-tumor activity [6]. This activity is increase if the PI3K and NFκB us inhibited simultaneously [7]. With the number of fluorine atoms with this molecule (3) PET imaging is potential a powerful tool for non-invasive monitoring of drug activity, synthesis and concept proof was provided with in investigation into a mouse model of colon cancer xenografts [8]. Outside of thyroid cancer the MEK inhibitor PD0325901 has shown activity in cell lines derived from malignant melanoma, in spite of BRaf mutations PD0325901 demonstrate anti growth activity in these cell lines [9], prompting the call for phase 1 trials with this compound as a single therapy and in combination with other tyrosine kinase inhibitors, most notable mTOR [10;11].

PD0325901: Clinical status

PD0325901 clinical trials at the phase I level were conducted in advanced cancers where the melanoma patients exhibited the more significant effect. However, dose level and scheduling was demonstrated to be difficult to pin down with any degree of certainty and further phase I were recommended. Any KRAS and BRaf mutations did not seem to inhibit the response to this molecule [12]. In a separate phase I trial with patients of advanced cancers of melanoma, breast and colon origin a similar conclusions was draw with one patient achieving complete response but again scheduling of the dose to avoid significant long term effects proved difficult [13]. A single phase II trial in NSCLC has been reported but the trial indicated that the end points had not been achieved with this treatment and the trial was ended early due to lack of response [14].

References

1. Solit DB, Garraway LA et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 2006; 439(7074):358-362.

2. Kohno M, Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy. Ann Med 2006; 38(3):200-211.

3. Adjei AA. The role of mitogen-activated ERK-kinase inhibitors in lung cancer therapy. Clin Lung Cancer 2005; 7(3):221-223.

4. Barrett SD, Bridges AJ et al. The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901. Bioorg Med Chem Lett 2008; 18(24):6501-6504.

5. Kinkade CW, Castillo-Martin M et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 2008; 118(9):3051-3064.

6. Leboeuf R, Baumgartner JE et al. BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines. J Clin Endocrinol Metab 2008; 93(6):2194-2201.

7. Liu D, Xing M. Potent inhibition of thyroid cancer cells by the MEK inhibitor PD0325901 and its potentiation by suppression of the PI3K and NF-kappaB pathways. Thyroid 2008; 18(8):853-864.

8. Leyton J, Smith G et al. Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer Ther 2008; 7(9):3112-3121.

9. Ciuffreda L, Del BD et al. Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations. Neoplasia 2009; 11(8):720-731.

10. Wee S, Jagani Z et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 2009; 69(10):4286-4293.

11. Hersey P, Bastholt L et al. Small molecules and targeted therapies in distant metastatic disease. Ann Oncol 2009; 20 Suppl 6:vi35-vi40.

12. LoRusso PM, Krishnamurthi SS et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res 2010; 16(6):1924-1937.

13. Boasberg PD, Redfern CH et al. Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. Cancer Chemother Pharmacol 2011; 68(2):547-552.

14. Haura EB, Ricart AD et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res 2010; 16(8):2450-2457.