Molecular pharmacology and antitumor activity of Zalypsis® in several human cancer cell lines

Abstract

Zalypsis ® is a new synthetic alkaloid tetrahydroisoquinoline antibiotic that has a reactive carbinolamine group. This functionality can lead to formation of a covalent bond with the amino group of selected guanines in the DNA double helix, both in the absence and in the presence of methylated cytosines. The resulting complex is additionally stabilized by the establishment of one or more hydrogen bonds with adjacent nucleotides in the opposite strand as well as by van der Waals interactions within the minor groove. Fluorescence-based thermal denaturation experiments demonstrated that the most favorable DNA triplets for covalent adduct formation are AGG, GGC, AGC, CGG and TGG, and these preferences could be rationalized on the basis of molecular modeling results. Zalypsis ®-DNA adducts eventually give rise to double-strand breaks, triggering S-phase accumulation and apoptotic cell death. The potent cytotoxic activity of Zalypsis ® was ascertained in a 24 cell line panel. The mean IC 50 value was 7 nM and leukemia and stomach tumor cell lines were amongst the most sensitive. Zalypsis ® administration in four murine xenograft models of human cancer demonstrates significant tumor growth inhibition that is highest in the Hs746t gastric cancer cell line with no weight loss of treated animals. Taken together, these results indicate that the potent antitumor activity of Zalypsis ® supports its current development in the clinic as an anticancer agent.

Anticancer Drugs That Interact with the DNA Minor Groove

“…87 Another related compound is PM00104 (Zalypsis ® ), an analog of the marine natural product jorumycin that blocks the minor groove of DNA after binding covalently to the amino group of several guanine residues, giving a complex that is further stabilized by hydrogen bonding with nucleotides in the opposite strand and van der Waals interactions. 88 This compound is in phase II of clinical trials for the treatment of multiple myeloma, bladder cancer, and Ewing sarcoma, as well as in early stage studies for a variety of additional solid and hematological tumor cell lines. 89 This name, although incorrect from the standpoint of chemical nomenclature, is usually employed to design a number of antitumor compounds that contain a cyclopropane ring fused to an indole system.…”

Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis

“…Zalypsis® (PM00104) is a marine-derived compound that has shown cytotoxic activity against various human tumor cell lines both in vitro and in vivo , including cell lines resistant to other chemotherapeutic agents [5,6]. Zalypsis is a novel antineoplastic agent currently in phase II clinical development in endometrial and cervical cancer, multiple myeloma, and Ewing’s sarcoma (http://clinicaltrials.gov/ct2/show/NCT01222767).…”

“…Trabectedin and Zalypsis exhibit overall similarities and sequence-specific differences in their DNA footprint properties [7]. In vitro data suggests that Zalypsis has DNA-binding properties, induces cell cycle arrest, and inhibits transcription, eventually leading to apoptosis [5,11]. Although the precise mechanism of action of this agent remains mostly unknown, there is increasing experimental data describing Zalypsis’ antitumoral activity [12,13].…”

“…Treatment of cells lines with Zalypsis leads to cell cycle delay in S phase, activation of the DNA damage checkpoint, and cell death. Additionally, Schizosaccharomyces pombe cells containing a RAD51 mutation were found to be extremely sensitive to Zalypsis, suggesting that the compound induces double-strand breaks (DSBs) [5]. Experiments in isogenic cell lines have indicated that the cytotoxic effect of this compound is independent of functional nucleotide excision repair system properties [7].…”

Zalypsis has in vitro activity in acute myeloid blasts and leukemic progenitor cells through the induction of a DNA damage response

“…17 Zalypsis (PM00104) is a new synthetic alkaloid related to jorumycin, renieramycins, safracins and saframycins. Zalypsis has demonstrated significant in vitro and in vivo activity against human solid and hematologic neoplasms via p53-dependent and p53-independent mechanisms, 18,19 and is currently being evaluated in early phase clinical trials on solid organ neoplasms and multiple myeloma.…”