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Chemistry and Biology of Tubulysins: Antimitotic Tetrapeptides with Activity Against Drug Resistant Cancers

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Chemistry and Biology of Tubulysins: Antimitotic Tetrapeptides with Activity Against Drug Resistant Cancers Natural Product Reports Chemistry and Biology of Tubulysins: Antimitotic Tetrapeptides with Activity against Drug Resistant Cancers Journal: Natural Product Reports Manuscript ID: NP-HIG-03-2014-000036.R2 Article Type: Highlight Date Submitted by the Author: 15-Jan-2015 Complete List of Authors: Murray, Bryan; University of Minnesota, Medicinal Chemistry Peterson, Michael; University of Minnesota, Medicinal Chemistry; Memorial Sloan-Kettering Cancer Center, Molecular Pharmacology and Chemistry Program Fecik, Robert; University of Minnesota, Medicinal Chemistry Page 1 of 9 Natural Product ReportsNatural Product Reports Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE Chemistry and Biology of Tubulysins: Antimitotic Tetrapeptides with Activity against Drug Resistant Cancers. Bryan C Murray, Michael T Peterson and Robert A Fecik* Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX 5 DOI: 10.1039/b000000x Since their first report in 2000, tubulysins have sparked great interest for development as anti-cancer agents due to their exceptionally potent anticancer activity. Progress in the discovery and development of tubulysins, especially tubulysin conjugates, has quickly advanced despite limitations in their availability from Nature. In this Highlight , the key research on the isolation and structure determination, biosynthesis, 10 bioactivity, structure activity relationships (SAR), synthesis, and conjugates of tubulysins is presented. Introduction only up to 1 mg/L of tubulysin D, 1 while Ar 315 and SBCb004 produce up to 41 and 0.48 3 mg/L, respectively. Tubulysins (1–14 , Figure 1 ) are antimitotic tetrapeptides isolated from myxobacteria reported by Höfle and co-workers in 2000. 1 A combination of degradation, NMR, and 13 C-enriched They have potent antiproliferative activity against human cancer 50 biosynthetic precursor feeding experiments were used to 15 cells, including drug-resistant cells, by inhibiting tubulin determine the structures of tubulysins A–I and the absolute polymerization. 1 A key issue that has stalled extensive study of configuration of the seven stereogenic centers.2,4 All tubulysins tubulysins is the extreme difficulty in obtaining the natural are comprised of N-methyl-D-pipecolinic acid (Mep), L- products from myxobacteria. isoleucine (Ile), and tubuvaline (Tuv), which contains an unusual 55 N,O -acetal and a secondary alcohol or acetoxy group. Tubulysins 20 Despite the scarce supply of tubulysins, their biological activity A–C, G, and I contain the C-terminal tubutyrosine (Tut) γ-amino and mechanism of action has been investigated. Extensive acid, while D, E, F and H instead have tubuphenylalanine (Tup) synthetic efforts on the total synthesis of tubulysins and analogs at this position (Figure 1 ). The X-ray structure of tubulysin A have yielded important insights on structure-activity relationships confirmed the original structure and absolute configuration (SAR). The more recent identification of the tubulysin 2 60 assignments. 25 biosynthetic gene cluster has also spurred research into metabolic engineering of the producing organisms. The X-ray and solution structures of tubulysin A in d -DMSO 6 and CD OD show the molecule in an extended conformation. 2 Since tubulysins effect their activity through a validated 3 Using transferred NOE data from the NOESY spectrum of an mechanism, they hold great clinical promise for the treatment of 65 aqueous tubulysin A-tubulin solution, the tubulin-bound 30 drug-resistant cancers. We review here the isolation and structure conformation was found to be compact with the aromatic thiazole determination, biosynthesis, biological activity, SAR, synthesis, and phenyl rings collapsed into a hydrophobic core with the N,O - and conjugates of this fascinating class of natural products. acetal and Ile side chain. 5 The crystal structure of a tubulysin bound to tubulin has yet to be reported. Isolation and Structure Determination Höfle and co-workers first reported in 2000 the isolation of four 70 Biosynthesis 35 members of the tubulysin family (A, B, D, and E) while screening Identification of the tubulysin biosynthetic gene cluster in A. myxobacterial culture extracts for biologically active disciformis An d48 was reported in 2004 6 and in Cystobacter sp. compounds.1 Tubulysins have extremely potent antiproliferative SBCb004 in 2010, 3 spurred by the potential to increase activity against cancer cells, including multidrug resistant KB-V1 1 fermentation titers and discover novel analogs through metabolic cervix carcinoma cells (tubulysin D, IC 50 = 0.08 ng/mL). 75 engineering and combinatorial biosynthesis. Tubulysins are 40 Archangium gephyra Ar 315 produces tubulysins A, B, C, G, and biosynthesized by a mixed nonribosomal peptide synthetase I, while Angiococcus disciformis An d48 produces tubulysins D, (NRPS)-polyketide synthase (PKS) system that incorporates E, F, and H.1,2 More recently a third producing myxobacterium, many unique and rare features. Many aspects of their biosynthesis Cystobacter SBCb004, was identified and also produces remain to be elucidated. The Tub NRPS-PKS comprises 7 tubulysins A, B, C, G, and I.3 Metabolite production in these 80 modules (2 PKS and 5 NRPS) on 5 proteins (TubB–F) that 45 wild-type strains is low, however. For instance, An d48 produces produces pretubulysin A (15 ) or D (16 ), which undergo tailoring This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 Natural Product Reports Page 2 of 9 oxidations and acylations to afford tubulysins and a host of other acid increased production to 0.66 and 1.76 µg/L. Pretubulysin A minor metabolites ( Figure 1). TubZ, responsible for synthesis of 60 production in M. xanthus (supplemented with D,L-pipecolinic the starter unit, L-pipecolinic acid, is also expressed in the acid) was much higher (190 µg/L), and additional metabolites biosynthetic gene cluster, as well as TubA, which is likely an could also be detected. 6,7 5 acyltransferase. Bioactivity Identification of the oxidases and other possible acyl transferases that carry out the tailoring reactions has proven difficult since The exceptional antiproliferative activity of tubulysins has led to there are no additional candidate genes expressed within the 65 a great deal of interest in evaluating their clinical potential and studying their mechanism of action. In growth inhibition assays 10 tubulysin biosynthetic gene cluster. Gene 633P1 in SBCb004 tubulysins were inactive against bacteria and yeasts, weakly encodes for a P450 monooxygenase that may carry out both active against fungi, and highly active against human cancer tailoring oxidations; SBCb004 with mutant 633P1 only produced 7 cells, including multidrug resistant cells that overexpress P- non-oxidized pretubulysin metabolites. 1,10 70 glycoprotein. The tubulysins have shown potent growth inhibition against breast,9 cervix,1,2 colon,10 leukemia,1 lung,11 15 There are several unusual aspects to tubulysin biosynthesis that melanoma, 10 ovarian,9 and prostate 10 cancer cells. In the NCI 60- deserve mention. The order of the domains in the two PKS human cancer cell line screen tubulysin A had an estimated GI modules (KS-AT-KR-DH-ER-ACP) is different from all other 50 6 for all cells of 12 nM; the lowest concentration tested (10 nM) known PKS systems (KS-AT-DH-ER-KR-ACP). Further, the 10 identification of over 20 new tubulysin metabolites shows that 75 was too high to establish a GI 50 for all cell lines. Additionally, tubulysins exhibit a degree of selectivity towards cancer cells due 20 many components of the pathway are imperfect in the processing 10,12 of chain elongation intermediates. 3 Among these new metabolites to their rapid division rates. are ones lacking the N-methyl group on tubuvaline, as previously 3 It was quickly established that the mechanism of action of observed with tubulysins U, V, X, and Z. Remarkably, skipping 80 tubulysins is inhibition of polymerization of the cytoskeletal of the NMT domain of module 3 in many cases leads to further protein tubulin and induction of apoptosis. 1,10 Binding 25 domain skipping of one or more of the β-carbon processing domains (KR, DH, ER) of PKS module 4 (see representative competition experiments with radiolabeled vinblastine and compound 17 , N-desmethyl 12-keto pretubulysin A, Figure 1). 3 colchicine revealed that tubulysin A binds to the peptide binding site located on β-tubulin near the Vinca alkaloid binding site.12 Metabolite 18 (Figure 1 ), tyrosine pretubulysin A, also indicates 85 Other natural products that bind to the peptide site include that the second PKS module 7 can be skipped in its entirety, dolastatin 10, hemiasterlin, cryptophycins, phomopsin A, and 30 suggesting that the intermediate following extension with phenylalanine or tyrosine by module 6 can be directly hydrolyzed others. A contributing mechanism of action may be anti- by the final TE domain. 3 Lastly, the tailoring oxidation and angiogenic effects. Tubulysin A exhibited strong anti-angiogenic effects, and was more potent than both paclitaxel and TNP-470 in acylation reactions are imperfect; all of the new metabolites 10 3 90 cord formation and cell migration assays. identified had bypassed one or more of these reactions. These 35 findings suggest that the Tub NRPS-PKS system has enormous The potential of tubulysin A for clinically relevant drug-drug potential for expanding the combinatorial biosynthetic toolbox. interactions has also been evaluated. Tubulysin A does not inhibit CYP1A2 and CYP2D6 in vitro (IC 50 s > 100 µM), and inhibits A new family of N-terminal docking domains in TubCdd from A. 10 95 CYP3A4 moderately (IC = 82 µM). Thus, the potential for 8 50 disciformis An d48 was described in 2008. TubCdd is drug-drug interactions involving these cytochrome P450s is low. 40 homodimeric, with an unusual fold containing an exposed β- hairpin that appears to be a key determinant of the interaction of Despite their exciting in vitro bioactivity profile, all tubulysins partner polypeptides that could be a docking code.8 This docking examined to date have proven to be extremely toxic in vivo .
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