AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts

Abstract

Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC 50 , 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC 50 range, 0.2-1.7 μmol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G 2 -M, S, and G 1 phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (maximum percentage tumor growth inhibition, range, 38-153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer 249 /Thr 252 , for up to 16 hours following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise.

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

“…In this latter model, following the guidelines used by clinicians to score response in solid tumors (39), we observed not only stasis but also tumor regression (with a "partial response" in 20-50% of evaluated tumors) and we believe this may be a significant finding in comparison with other latest-generation CDKIs. Several "evolved" CDK2 inhibitors, such as R547 (40), P276-00 (41), AT7519 (42), and AZD5438 (43), are reported to be in late preclinical or clinical testing, but we believe PHA-848125 is unique in possessing the combined properties reported here of good oral bioavailability, capacity to induce tumor regression, and flexibility of treatment scheduling, as shown in the DMBA-induced mammary carcinoma model. Notably, in all preclinical efficacy experiments, PHA-848125 was well tolerated without overt signs of toxicity.…”

Selective Pharmacologic Inhibition of a PASTA Kinase Increases Listeria monocytogenes Susceptibility to β-Lactam Antibiotics

“…To determine if more selective kinase inhibitors could function to sensitize L. monocytogenes to ␤-lactam antibiotics, we screened a small library of kinase inhibitors for ␤-lactam-dependent inhibition of L. monocytogenes growth. We identified one compound, AZD5438 (a cyclin-dependent kinase [CDK] inhibitor [29]), capable of inhibiting L. monocytogenes growth in a ␤-lactam-synergism-dependent manner (Fig. 5A).…”

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs

“…Gossypin (Texas Biomedical Research Institute)Dual BRAF-CDK4/6 pathway inhibitor CDK4 IC50 = 3.9nM CDK6 IC 50 = 9.8nM ARK5 IC 50 = 5nM FLT3 IC 50 = 12nM FYN IC 50 = 11nM FMS IC 50 = 10nM PDGFRβ IC 50 = 26nM FGFR1 IC 50 = 26nM ABL IC 50 = 53nM PI3Kδ IC 50 = 144nMFigure 13: BAY-1000294 (Roniciclib, Bayer). Optimization of 2-Amino-pyrimidin-4-phenyl-sulfonamide core as multitarget CDK-based inhibitor.5d CDK4 IC 50 = 2nM CDK1 IC 50 = 3.2uM FLT3 IC 50 = 2nM Colo205 IC 50 (Rb + ) = 10nM MOLM13 IC 50 (FLT3 ITD ) = 10nM F% = 44 CDK4 IC 50 = 3nM CDK1 IC 50 = 2.2uM FLT3 IC 50 = 1nM Colo205 IC 50 (Rb + ) = 55nM MOLM13 IC 50 (FLT3 ITD ) = 19nM F% = 75…”

“…6bCDK2 IC50 = 10nM CDK1 IC 50 = 10nM VEGF-R2 IC 50 = 59nM CA-II IC 50 = 403nM MFC7 IC 50 = 30nM ZK-304709 CDK2 IC 50 = 4nM CDK1 IC 50 = 500nM VEGF-R2 IC 50 = 34nM CA-II IC 50 = 514nM MFC7 IC 50 = 266nM BAY-1000394 (Roniciclib) CDK2 IC 50 = 9nM CDK1 IC 50 = 7nM VEGF-R2 IC 50 = 163nM CA-II IC 50 > 10uM MFC7 IC 50 = 15nM…”

“…AT7519CDK2 IC50 = 0.047uM CDK5 IC 50 = 0.013uM CDK9 IC 50 <10nM HCT116 IC 50 = 0.08uM m-Plasma clearance 40ml/min/kg 10e CDK2 IC 50 = 0.14uM CDK1 IC 50 = 0.98uM HCT116 IC 50 = 0.3uM m-Plasma clearance 40ml/min/kg 10d CDK2 IC 50 = 0.03uM LE 0.45 HCT116 1.4uM 9c CDK2 IC 50 = 150nM JAK2 IC 50 = 3.3uM FLT3 IC 50 = 2.9uM 9b CDK2 IC 50 = 2.6uM JAK2 IC 50 = 1.7uM FLT3 IC 50 = 1uM 9d CDK2 IC 50 = 21nM JAK2 IC 50 = 150nM FLT3 IC 50 = 110nM…”