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Target Overview
Cyclin-dependent kinase 2 (CDK2) is a serine/threonine kinase activated via interaction with cyclin E or cyclin A, driving G1/S and S phase progression of the cell cycle.
CDK2 inhibition has the potential to address multiple resistance mechanisms to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors that are standard-of-care in estrogen receptor positive (ER+) advanced breast cancer, including overexpression or amplification of cyclin E1 (CCNE1), MYC activation, phosphatase and tensin homolog (PTEN) loss, retinoblastoma 1 (RB1) loss, and cyclin-dependent kinase inhibitor 1A (CDKN1A) activity.1-4
In addition, CCNE1 is frequently amplified and overexpressed in cancers including ovarian, uterine, breast, gastric and others, with preclinical data linking CDK2 inhibition sensitivity to high CCNE1.5,6
Compound Overview
AZD8421 is a potent and highly selective CDK2 inhibitor that is being clinically evaluated in patients with ER+ HER2- advanced breast cancer and patients with metastatic high-grade serous ovarian cancer.
Mechanism of Action
References
1. Costa C, Wang Y, Ly A, et al. Cancer Discov. 2020;10(1):72-85. 2. Freeman-Cook K, Hoffman R, Miller N, et al. Cancer Cell. 2021;39(10):1404-1421. 3. Herrera-Abreu MT, Palafox M, Asghar U, et al. Cancer Res. 2016;76(8):2301-2313. 4. Kumarasamy V, Vail P, Nambiar R, Witkiewicz AK, Knudsen ES. Cancer Res. 2021;81(5):1347-1360. 5. Otto T, Sicinski P. Nat Rev Cancer. 2017;17(2):93-115. 6. Kanska J, Zakhour M, Taylor-Harding B, Karlan BY, Wiedemeyer WR. Gynecol Oncol. 2016;143(1):152-158.
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Abbreviations
CCNE1/ CycE
cyclin E1
CDK
cyclin-dependent kinase
CDK2
cyclin-dependent kinase 2
CDKN1A
cyclin-dependent kinase inhibitor 1A
E2F
transcription factor E2F
ER+
estrogen receptor positive
G1 phase
gap/growth phase I
G1/S
gap/growth phase I/DNA synthesis phase
G2 phase
gap/growth phase II
HER2-
human epidermal growth factor receptor 2 negative
M phase
mitotic phase
PTEN
phosphatase and tensin homolog
RB1
retinoblastoma 1
S phase
DNA replication phase
Target Overview
Cyclin-dependent kinase 2 (CDK2) is a serine/threonine kinase activated via interaction with cyclin E or cyclin A, driving G1/S and S phase progression of the cell cycle.
CDK2 inhibition has the potential to address multiple resistance mechanisms to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors that are standard-of-care in estrogen receptor positive (ER+) advanced breast cancer, including overexpression or amplification of cyclin E1 (CCNE1), MYC activation, phosphatase and tensin homolog (PTEN) loss, retinoblastoma 1 (RB1) loss, and cyclin-dependent kinase inhibitor 1A (CDKN1A) activity.1-4
In addition, CCNE1 is frequently amplified and overexpressed in cancers including ovarian, uterine, breast, gastric and others, with preclinical data linking CDK2 inhibition sensitivity to high CCNE1.5,6
Compound Overview
AZD8421 is a potent and highly selective CDK2 inhibitor that is being clinically evaluated in patients with ER+ HER2- advanced breast cancer and patients with metastatic high-grade serous ovarian cancer.
Mechanism of Action
References
1. Costa C, Wang Y, Ly A, et al. Cancer Discov. 2020;10(1):72-85. 2. Freeman-Cook K, Hoffman R, Miller N, et al. Cancer Cell. 2021;39(10):1404-1421. 3. Herrera-Abreu MT, Palafox M, Asghar U, et al. Cancer Res. 2016;76(8):2301-2313. 4. Kumarasamy V, Vail P, Nambiar R, Witkiewicz AK, Knudsen ES. Cancer Res. 2021;81(5):1347-1360. 5. Otto T, Sicinski P. Nat Rev Cancer. 2017;17(2):93-115. 6. Kanska J, Zakhour M, Taylor-Harding B, Karlan BY, Wiedemeyer WR. Gynecol Oncol. 2016;143(1):152-158.
Clinical trial information
Select trial for more information
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Abbreviations
CCNE1/ CycE
cyclin E1
CDK
cyclin-dependent kinase
CDK2
cyclin-dependent kinase 2
CDKN1A
cyclin-dependent kinase inhibitor 1A
E2F
transcription factor E2F
ER+
estrogen receptor positive
G1 phase
gap/growth phase I
G1/S
gap/growth phase I/DNA synthesis phase
G2 phase
gap/growth phase II
HER2-
human epidermal growth factor receptor 2 negative
M phase
mitotic phase
PTEN
phosphatase and tensin homolog
RB1
retinoblastoma 1
S phase
DNA replication phase