Novel Small Molecule Cyclin-Dependent Kinases Modulators in Human Clinical Trials

• Published in: Cancer biology & therapy 2003-07, Vol.2 (4 Suppl 1), p.83-94
• Main Author: Senderowicz, Adrian M.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Antineoplastic Agents - pharmacology; Binding Sites; Cell Cycle - drug effects; Cell Division - drug effects; Clinical Trials as Topic; Cyclin-Dependent Kinases - antagonists & inhibitors; Enzyme Inhibitors - pharmacology; Humans; Models, Biological; Models, Chemical; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - metabolism; Retinoblastoma Protein - metabolism
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.207

Aberrations in cell cycle control occurs in the majority of human malignancies due to inactivation of tumor suppressor gene Rb by the phosphorylation induced by "hyperactive" cyclin-dependent kinases. Thus, it is quite reasonable to design cdk modulators for the prevention and treatment of human neoplasms. In order to target the cdk complexes, 2 main strategies were considered: to target the ATP binding site of cdks (direct cdk modulators) and to target upstream pathways required for cdk activation (indirect cdk modulators). Examples for the first group include flavopiridol, roscovitine, BMS-387032. Examples for the second group include perifosine, lovastatin, UCN-01. The first example of a direct small molecule cdk modulator tested in the clinic, flavopiridol, is a pan-cdk inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation and has antiangiogenic properties. Clinical trials with this agent were performed with at least 3 different schedules of administration: 1 hour infusion, 24 hour infusion and 72 hour infusion. Main toxicities for infusions >=24 hours are secretory diarrhea and pro-inflammatory syndrome. In addition, patients receiving shorter infusions have nausea/vomiting and neutropenia. Some clinical responses were observed in several patients with refractory malignancies. Based on these encouraging results, a Phase 3 trial comparing standard combination chemotherapy versus combination chemotherapy plus flavopiridol is currently under investigation. The second example of direct small molecule cdk modulator tested in clinical trials is UCN-01 (7-hydroxi-staurosporine). UCN-01 has interesting preclinical features: inhibits ca2+-dependent PKCs, promotes apoptosis, arrest cell cycle progression at G1/S and abrogates checkpoints upon DNA damage. The first Phase I trial of UCN-01 demonstrated a very prolonged half-life. Based on this novel feature, UCN-01 is administered as a 72 hour continuous infusion every 4 weeks (second and subsequent cycles UCN-01 is administered as a 36-hour infusion). Other shorter schedules (i.e,. 3 hours) are being tested. Dose-limiting toxicities include nausea/vomiting, hypoxemia and insulin-resistant hyperglycemia. Combination trials with cisplatin and other DNA-damaging agents are being tested. Recently, Phase I trials with two novel small molecule cdk modulators, BMS 387032 and R-Roscovitine (CYC202), have commenced with good tolerability.