Actually, by using a yeast two hybrid system, our previous study has identified

Several CDK inhibitors have been evaluated in phase 1 clinical trials, but none has demonstrated significant mono therapy activity in solid tumor patients, despite strong preclinical data to support their use. The lack of correl ation of antitumor activity observed in vitro and in vivo, groups to determine the predictive ABT-737 Bcl-2 阻害剤 response to CDK inhibitors. Preclinical and phase 2 studies have associated elevated expression of Rb protein, luminal ER subtype, and reduced P16 expression with sensitivity to PD033299, a selective inhibitor of CDK4 6, CDK4 CDK6 inhibitors shut down Rb phosphorylation, therefore, re sponses are precluded in tumor cells that lack Rb. In contrast, to our knowledge, a clear predictive biomarker profile for broad CDK inhibitors has not been identified.



The development of flavopiridol was marked AEB071 PKC 阻害剤 by dose lAG-014699 PF-01367338 imiting diarrhea in both 72 hour continuous infusion trials, and by dose limiting neutropenia using the daily 1 hour infusion schedule, Several newer CDK inhibitors, such as PD0332991, have also resulted in DLTs of neutropenia, Neutropenia as a DLT has been seen with dinaciclib using higher doses on a once every 21 days dosing schedule, Dose limiting toxicities with seliciclib, administered orally twice daily for 7 days of a 21 day schedule, were similar to those observed with dinaciclib using the once weekly dosing schedule, including hypokalemia, hyponatremia, elevated gamma glutamyl transferase, hyperglycemia, and vascu litic rash, The first in human trial of PHA793887 administered as a 1 hour infusion on days 1, 8, and 15 in a 4 week cycle resulted in a patient with fatal hepatorenal failure at the third dose level of 44 mg m2 and a patient with grade 4 hepatic failure at the next dose level of 66 mg m2, which led the sponsor to discontinue further development of this agent, Development of AZD5438 was also discontinued due to high variability and unpre dictable drug exposure combined with a lack of objective responses, Interestingly AZD5438 was studied first in healthy volunteers with DLT of nausea and vomiting with a single dose of 160 mg , similar AZD5438 exposures were not tolerated using various continuous daily dosing schedules in the phase 1 trial in Several preliminary reports from phase 1 clinical trials have demonstrated enhanced antitumor activity when CDK inhibitors are combined with cytotoxic agents, in patients with both advanced solid tumors and estrogen receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer, Ini tial results from an ongoing phase 2 trial examining the combination of PD 0332991 and letrozole in ER HER2 breast cancer patients showed significant improvements in progression free survival, as well as higher response and clinical benefit rates with the combination compared with letrozole alone, Preclinical studies using tumor cell lines have also shown promising results when CDK inhibitors have been used in combination with other targeted therapies, such as histone deacetylase inhibitors and AKT inhibitors, In early phase clinical trials, dinaciclib has also shown encouraging results as monotherapy in CLL at the RP2D, indicating dinaciclib may also be effective in some hema tologic malignancies.