Meriolins, a New Class of Cell Death–Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases

Abstract

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1A, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms. [Cancer Res 2007;67(17):8325-34]

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

“…CDK1/cyclin B (M-phase starfish oocytes, native), CDK2/ cyclin A, CDK2/cyclin E, CDK5/p25, and CDK7/cyclin H (human, recombinant) were prepared as described previously (44). Their kinase activity was assayed in buffer C, with 1 mg histone H1/mL, in the presence of 15 Amol/L [g- 33 P]ATP (3,000 Ci/mmol; 10 mCi/mL) in a final volume of 30 AL.…”

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

“…However, the inhibition of CDK9 (IC50 26 nM) was determined to be even more potent than that of either CDK1 (IC50 60 nM) or CDK2 (IC50 80 nM). Strong inhibition by variolin B of several other kinases was observed, including casein kinase-1 (CK1), FMS-like tyrosine kinase 3, and glycogen synthase kinase-3 (GSK3) [7,8]. The unique heterocyclic framework of variolin thus emerged as a new scaffold for the design of new inhibitors of CDKs.…”

“…A new class of 7-azaindole-containing analogues have been thus designed and the term "meriolin" has been coined to describe this hybrid structure ( Figure 4) [7,8]. Meriolins (22)(23)(24)(25) display potent inhibitory activity and relative selectivity toward CDKs and also exhibit better antiproliferative and proapoptotic properties in cell cultures than their ''inspirational parent'' molecules.…”

“…Meriolin 3 (24) potently inhibits tumor growth in two mouse xenograft models, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new kinase-inhibitory scaffold with promising antitumor activity derived from molecules initially isolated from marine organisms [7]. (22)(23)(24)(25).…”

“…It was found to be cytotoxic against L-1210 murine leukemia cells in vitro with IC50 value of 0.39 μg/mL. Delfourne et al, synthesized an isomer of ascididemin, named as 9H-quino[4,3,2-de] [1,7]phenanthroline-9-one (124) [124]. These compounds were tested in vitro at six different concentrations on 12 different human cancer cell lines such as glioblastomas, breast, colon, lung, prostate, and bladder cancers.…”