AS703026 plays a significant role in MEK1 and MEK2
CHEMISTRY AND MODE OF ACTION
AS703026 is veryprecise in action and acts like a noncompetitive inhibitor of MEK1/2 [1]. This little molecule is becoming tested for its efficacy in phase I clinical trials. AS703026 was located to be productive at a concentration of 0.005 to twomuch more potent inhibitor than AZD6244. It could control the osteoclast differentiation induced by cytokines in a better way (9-10 timeshigher potent than AZD6244).
AS703026: ACTION ON KRAS
MEK1/2 followed by ERK1/2 signaling pathways get constitutively activated by the mutations of Kirsten ras sarcoma viral oncogene (KRAS) or B-type Raf kinase (compound library). Colorectal cancer cell lines frequently show BRAF or KRAS mutations which activate ERK1/2 followed by the activation of the PI3K pathway. Inhibitors which target MEK1/2 are extremelyeffectiveinside the cells which show high levels of ERK1/2 [2]. The colorectal cancer cells showed an awesome resistance towards anti EGFR antibodies plus themajor mechanism behind this was the mutations of KRAS and ABRF. The colorectal cancer cells showed an excellent resistance towards anti EGFR monoclonal antibodies and themajor mechanism behind this was the mutations of KRAS and BRAF. MEK or MAP2K lies downstream of BRAF inside the signaling cascade of epidermal growth factor receptor (RAS-RAF-MEK). MEK utilizes ERK as its substrate [3]. KRAS mutant cells are identified to be much less sensitive to MEK inhibitors than BRAF mutant cell lines. Hence those cells which show BRAF mutations are likelyto getadditional inhibited by AS703026. This inhibitor has been studied in tumor xenografts and has been located that it could pose challenge towards the resistance induced by the mutations of K-ras to EGFR mAb in case of colorectal cancer cell lines [5]
AS703026: ACTION ON CELL PROLIFERATION
All of the growth factors and cytokines which act by way of tyrosine kinase receptors, cytokine receptors or GPCRs activate ERK1/2 MAP kinases [4]. Inhibition of ERK1/2 arrests the progression of the cell cycle from the G0/G1 to S phase [4]. Hence blocking ERK having asmall molecule inhibitor of MEK1/2 checks the proliferation of several cancerous cells. These inhibitors were also discoveredsuccessful in mouse xenograft models.
CONCLUSION
AS703026 is really ahighly potent in checking the cancerous growth. It checks the activation of MEK1/2 dependent proteins. It controls the action of transcription aspects also which in turn controls the cancerous cell?¡¥s proliferation.
REFERENCES
1. Delord J, Houede N, et al. First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors. J Clin Oncol 2010; 28:15s, (suppl; abstr 2504).
2. Balmanno K, Chell SD, et al. Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer 2009 Nov 15; 125(10):2332-41.
3. Kevin M. Sullivan, et al. Impact of KRAS Mutations on Management of Colorectal Carcinoma. Patholog Res Int 2011; 2011: 219309.
4. Fremin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol 2010; 3: 8.
5. Yoon J, Koo KH, Choi KY. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res 2011 Jan 15; 71(2):445-53.
Related Posts :
PLX-4032 (RG7204) – THE MELANOMA CURE
BIRB 796 : ENHANCES THE EFFECT OF BORTEZOMIB
AS703026 is veryprecise in action and acts like a noncompetitive inhibitor of MEK1/2 [1]. This little molecule is becoming tested for its efficacy in phase I clinical trials. AS703026 was located to be productive at a concentration of 0.005 to twomuch more potent inhibitor than AZD6244. It could control the osteoclast differentiation induced by cytokines in a better way (9-10 timeshigher potent than AZD6244).
AS703026: ACTION ON KRAS
MEK1/2 followed by ERK1/2 signaling pathways get constitutively activated by the mutations of Kirsten ras sarcoma viral oncogene (KRAS) or B-type Raf kinase (compound library). Colorectal cancer cell lines frequently show BRAF or KRAS mutations which activate ERK1/2 followed by the activation of the PI3K pathway. Inhibitors which target MEK1/2 are extremelyeffectiveinside the cells which show high levels of ERK1/2 [2]. The colorectal cancer cells showed an awesome resistance towards anti EGFR antibodies plus themajor mechanism behind this was the mutations of KRAS and ABRF. The colorectal cancer cells showed an excellent resistance towards anti EGFR monoclonal antibodies and themajor mechanism behind this was the mutations of KRAS and BRAF. MEK or MAP2K lies downstream of BRAF inside the signaling cascade of epidermal growth factor receptor (RAS-RAF-MEK). MEK utilizes ERK as its substrate [3]. KRAS mutant cells are identified to be much less sensitive to MEK inhibitors than BRAF mutant cell lines. Hence those cells which show BRAF mutations are likelyto getadditional inhibited by AS703026. This inhibitor has been studied in tumor xenografts and has been located that it could pose challenge towards the resistance induced by the mutations of K-ras to EGFR mAb in case of colorectal cancer cell lines [5]
AS703026: ACTION ON CELL PROLIFERATION
All of the growth factors and cytokines which act by way of tyrosine kinase receptors, cytokine receptors or GPCRs activate ERK1/2 MAP kinases [4]. Inhibition of ERK1/2 arrests the progression of the cell cycle from the G0/G1 to S phase [4]. Hence blocking ERK having asmall molecule inhibitor of MEK1/2 checks the proliferation of several cancerous cells. These inhibitors were also discoveredsuccessful in mouse xenograft models.
CONCLUSION
AS703026 is really ahighly potent in checking the cancerous growth. It checks the activation of MEK1/2 dependent proteins. It controls the action of transcription aspects also which in turn controls the cancerous cell?¡¥s proliferation.
REFERENCES
1. Delord J, Houede N, et al. First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors. J Clin Oncol 2010; 28:15s, (suppl; abstr 2504).
2. Balmanno K, Chell SD, et al. Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer 2009 Nov 15; 125(10):2332-41.
3. Kevin M. Sullivan, et al. Impact of KRAS Mutations on Management of Colorectal Carcinoma. Patholog Res Int 2011; 2011: 219309.
4. Fremin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol 2010; 3: 8.
5. Yoon J, Koo KH, Choi KY. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res 2011 Jan 15; 71(2):445-53.
Related Posts :
PLX-4032 (RG7204) – THE MELANOMA CURE
BIRB 796 : ENHANCES THE EFFECT OF BORTEZOMIB
