Synthesis and Evaluation of Linear and Macrocyclic Dolastatin 10 Analogues Containing Pyrrolidine Ring Modifications

Akaiwa, Michinori; Martin, Tioga J.; Mendelsohn, Brian A.

doi:10.1021/acsomega.8b00093

Cited by 16 publications

(23 citation statements)

References 32 publications

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“…It is a structurally-modified analogue of the natural dolastatin 10 [50], a potent antineoplastic pentapeptide (785.1 Da) isolated from the marine mollusk dolabella auricularia by Pettit et al in 1987 [51]. MMAE comprises the following four amino acid residues: dolavaline (Dov), Val, dolaisoleuine (Dil), dolaproine (Dap), and the C-terminal amine dolaphenine (Doe) [52]. Figure 8 shows the structural differences between the synthetic MMAE analogue (A) and the natural pentapeptide dolastatin 10 (B).…”

Section: Enfortumab Vedotin-ejfv (Padcev Tm )mentioning

confidence: 99%

2019 FDA TIDES (Peptides and Oligonucleotides) Harvest

et al. 2020

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2019 has been an excellent year in terms of peptides and oligonucleotides (TIDES) approved by the FDA. Despite the drop in the number of total drugs approved by the FDA in 2019 in comparison with 2018 (48 vs. 59), the total number of TIDES authorized increased (seven vs. three). Year after year, TIDES are increasingly present in therapy, as imaging agents, theragnostic and constituent moieties of other complex drugs, such as antibody drug conjugates. This means a consolidation of these kinds of drugs in the pharmaceutical arena, paving the way in the coming years for the approval of others for diverse medical indications. Here the TIDES approved in 2019 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.

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Section: Enfortumab Vedotin-ejfv (Padcev Tm )mentioning

confidence: 99%

2019 FDA TIDES (Peptides and Oligonucleotides) Harvest

et al. 2020

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“…First, we created a set of auristatin compounds containing heteroatoms in the central core amino acids and evaluated them to determine whether heteroatom introduction could be an effective approach to control cytotoxic activity and serve as a handle for new linker attachment at P2 or P4 instead of at P1 or P5. 18,19) 3.2.…”

Section: Central Peptide Modificationmentioning

confidence: 99%

“…We investigated SAR for analogues containing heteroatoms and other non-natural amino acids in the P2 position. 18) The functional groups chosen for incorporation in the P2 amino acid unit were amine, azide, hydroxyl, and thiol. From a membrane permeability standpoint, P2 modified analogues with Lphenylalanine (Phe) methyl ester at the P5 unit were compared (Fig.…”

Section: P2 Modificationmentioning

confidence: 99%

“…11,16) Thus auristatins are attractive toxic compounds on ADCs and we also have investigated the structure-activity relationship (SAR) and auristatins ADCs to create the next generation ADCs. [17][18][19][20] In this review, our recent research regarding auristatin analogues is described. The first section discusses N-terminal (P1) and C-terminal (P5) modifications and corresponding ADC data.…”

Section: Introductionmentioning

confidence: 99%

“…17) The second section discusses central peptide (P2-P4) modifications, focusing on P2 and P4 SAR. [18][19][20]…”

Section: Introductionmentioning

confidence: 99%

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Antibody–Drug Conjugate Payloads; Study of Auristatin Derivatives

2020

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Auristatins are important payloads used in antibody drug conjugates (ADCs), and the most well-known compound family member, monomethyl auristatin (MMAE), is used in two Food and Drug Administration (FDA)-approved ADCs, Adcetris ® and Polivy ®. Multiple other auristatin-based ADCs are currently being evaluated in human clinical trials and further studies on this class of molecule are underway by several academic and industrial research groups. Our group's main focus is to investigate the structure-activity relationships (SAR) of novel auristatins with the goal of applying these to next generation ADCs. Modifications of the auristatin backbone scaffold have been widely reported in the chemical literature focusing on the terminal subunits: P1 (N-terminus) and P5 (C-terminus). Our approach was to modulate the activity and hydrophilic character through modifications of the central subunits P2-P3-P4 and thorough SAR study on the P5 subunit. Novel hydrophilic auristatins were observed to have greater potency in vitro and displayed enhanced in vivo antitumor activity when conjugated via protease-cleavable linkers and delivered intracellularly. Analysis of ADC aggregation also indicated that novel hydrophilic payloads enabled the synthesis of high-drug-to-antibody ratio (DAR) ADCs that were resistant to aggregation. Modification of the central peptide subunits also resulted in auristatins with potent cytotoxic activity in vitro and these azide-modified auristatins contain a handle for linker attachment from the central portion of the auristatin backbone.

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Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing

et al. 2020

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Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody‐drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non‐pathological cells proximal to the tumour (“bystander killing”). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz‐azastatin methyl ester, which included the C2‐elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz‐protected azastatin methyl ester (0.13–3.0 nM) inhibited proliferation more potently than MMAE (0.47–6.5 nM), removal of the Cbz‐group yielded dramatically increased IC50‐values (9.8–170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next‐generation ADC development.

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Synthesis and Evaluation of Linear and Macrocyclic Dolastatin 10 Analogues Containing Pyrrolidine Ring Modifications

Cited by 16 publications

References 32 publications

2019 FDA TIDES (Peptides and Oligonucleotides) Harvest

2019 FDA TIDES (Peptides and Oligonucleotides) Harvest

Antibody–Drug Conjugate Payloads; Study of Auristatin Derivatives

Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing

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