Cytotoxic Simplified Tubulysin Analogues

Raghavan, Bhooma; Balasubramanian, Ranganathan; Steele, Jaeson C.; Sackett, Dan L.; Fecik, Robert

doi:10.1021/jm701321p

Cited by 56 publications

(33 citation statements)

References 24 publications

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“…The tubulysins are a compelling drug class for ADCs as they are highly potent across a wide range of cancer cell lines and retain potency on MDR þ cell lines like L428 and 786-O (Table 1). We and others (15) have demonstrated that a secondary amine at the N-terminus of two distinct tubulysin analogues significantly impairs cytotoxic activity relative to the N-methylated tertiary amine parent compounds. Conversion of the C-terminal carboxylate to include a circulation-stable conjugatable group appears more promising.…”

Section: Discussionmentioning

confidence: 78%

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Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates

Burke

Hamilton

Pires

et al. 2016

Molecular Cancer Therapeutics

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A quaternary ammonium-based drug-linker has been developed to expand the scope of antibody-drug conjugate (ADC) payloads to include tertiary amines, a functional group commonly present in biologically active compounds. The linker strategy was exemplified with a b-glucuronidase-cleavable auristatin E construct. The drug-linker was found to efficiently release free auristatin E (AE) in the presence of b-glucuronidase and provide ADCs that were highly stable in plasma. Anti-CD30 conjugates comprised of the glucuronide-AE linker were potent and immunologically specific in vitro and in vivo, displaying pharmacologic properties comparable with a carbamate-linked glucuronide-monomethylauristatin E control. The quaternary ammonium linker was then applied to a tubulysin antimitotic drug that contained an N-terminal tertiary amine that was important for activity. A glucuronide-tubulysin quaternary ammonium linker was synthesized and evaluated as an ADC payload, in which the resulting conjugates were found to be potent and immunologically specific in vitro, and displayed a high level of activity in a Hodgkin lymphoma xenograft. Furthermore, the results were superior to those obtained with a related tubulysin derivative containing a secondary amine N-terminus for conjugation using previously known linker technology. The quaternary ammonium linker represents a significant advance in linker technology, enabling stable conjugation of payloads with tertiary amine residues.Mol Cancer Ther; 15(5); 938-45. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 78%

“…However, modification of tubulysins to introduce a functional group for conjugation is commonly not well tolerated. For example, the N-terminal Ndesmethyl analogue of a keto-tubulysin derivative was found to be 100-fold less potent than the tertiary amine-containing parent (15). Similarly, conversion of N…”

Section: Introductionmentioning

confidence: 99%

Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates

Burke

Hamilton

Pires

et al. 2016

Molecular Cancer Therapeutics

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“…Competition studies suggest a binding site close to the peptide site of the vinca domain of β tubulin (Khalil et al ., 2006). Due to the limited natural supply of tubulysin and its complicated synthesis, clinical development has, to date, been hampered (Raghavan et al ., 2008). By studying the pathway of tubulysin biosynthesis in myxobacteria, Prt was first postulated and then identified as a biosynthetic intermediate (Ullrich et al ., 2009a) that is synthetically accessible, and can be easily derivatized (Ullrich et al ., 2009b; Burkhart et al ., 2011).…”

Section: Discussionmentioning

confidence: 99%

“…A novel group of microtubule‐depolymerizing natural products of myxobacterial origin, the tubulysins, has recently been described (Sasse et al ., 2000), and has turned out to be highly potent against some tumour cell lines (Sasse et al ., 2000; Kaur et al ., 2006). Due to the supply issue mentioned earlier, several attempts have been made to synthesize simplified tubulysin derivatives (Raghavan et al ., 2008; Ullrich et al ., 2009a). The most promising approach to date is the synthesis of pretubulysin (Prt), a putative precursor of some tubulysins, which has only a slight loss of potency as compared to tubulysin itself (Ullrich et al ., 2009a).…”

Section: Introductionmentioning

confidence: 99%

Anti‐angiogenic effects of the tubulysin precursor pretubulysin and of simplified pretubulysin derivatives

Rath

Liebl

Fürst

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSEThe use of tubulin-binding compounds, which act in part by inhibiting tumour angiogenesis, has become an integral strategy of tumour therapy. Recently, tubulysins were identified as a novel class of natural compounds of myxobacterial origin, which inhibit tubulin polymerization. As these compounds are structurally highly complex, the search for simplified precursors [e.g. pretubulysin (Prt)] and their derivatives is mandatory to overcome supply problems hampering clinical development. We tested the anti-angiogenic efficacy of Prt and seven of its derivatives in comparison to tubulysin A (TubA). EXPERIMENTAL APPROACHThe compounds were tested in cellular angiogenesis assays (proliferation, cytotoxicity, cell cycle, migration, chemotaxis, tube formation) and in vitro (tubulin polymerization). The efficacy of Prt was also tested in vivo in a murine subcutaneous tumour model induced with HUH7 cells; tumour size and vascularization were measured. KEY RESULTSThe anti-angiogenic potency of all the compounds tested ran parallel to their inhibition of tubulin polymerization in vitro. Prt showed nearly the same efficacy as TubA (EC50 in low nanomolar range in all cellular assays). Some modifications in the Prt molecule caused only a moderate drop in potency, while others resulted in a dramatic loss of action, providing initial insight into structure-activity relations. In vivo, Prt completely prevented tumour growth and reduced vascular density to 30%. CONCLUSIONS AND IMPLICATIONSPrt, a chemically accessible precursor of some tubulysins is a highly attractive anti-angiogenic compound both in vitro and in vivo. Even more simplified derivatives of this compound still retain high anti-angiogenic efficacy. AbbreviationsHMEC-1, human dermal microvascular endothelial cells; HUVECs, human umbilical vein endothelial cells; PI, propidium iodide; Prt, pretubulysin; TubA, tubulysin A

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“…9-11 However, the structural complexity of natural products, such as intricate ring systems and numerous chiral centers, may lead to limited supplies and hamper mechanism of action studies and clinical development 12. For this reason, structural simplification of natural products is a powerful and highly productive tool for lead development and analog design 13. A well-known example is the simplification of morphine, which led to the clinically used medicines levophanol and meperidine 14.…”

Section: Introductionmentioning

confidence: 99%

Antitumor agents 270. Novel substituted 6-phenyl-4H-furo[3,2-c]pyran-4-one derivatives as potent and highly selective anti-breast cancer agents

Dong

Shi

Nakagawa‐Goto

et al. 2010

Bioorganic & Medicinal Chemistry

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6-Phenyl-4H-furo[3,2-c]pyran-4-one derivatives based on neo-tashinlactone (1) were synthesized and evaluated as novel anti-breast cancer agents. Compounds 10-13, 23, 25, and 27 showed potent inhibition against the SK-BR-3 breast cancer cell line. Importantly, 25 and 27 showed the highest cancer cell line selectivity, being approximately 100- to 250-fold more potent against SK-BR-3 (ED50 0.28 and 0.44 μM, respectively) compared with other cancer cell lines tested. In addition, 25 displayed low cytotoxicity against normal breast cell lines 184A1 and MCF10A. Compounds 25 and 27 merit further investigation in our continuing program to generate and develop selective anti-breast cancer agents.

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Cytotoxic Simplified Tubulysin Analogues

Cited by 56 publications

References 24 publications

Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates

Development of Novel Quaternary Ammonium Linkers for Antibody–Drug Conjugates

Anti‐angiogenic effects of the tubulysin precursor pretubulysin and of simplified pretubulysin derivatives

Antitumor agents 270. Novel substituted 6-phenyl-4H-furo[3,2-c]pyran-4-one derivatives as potent and highly selective anti-breast cancer agents

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