3 research outputs found
Development of a New Benzophenone–Diketopiperazine-Type Potent Antimicrotubule Agent Possessing a 2‑Pyridine Structure
A new benzophenone–diketopiperazine-type
potent antimicrotubule
agent was developed by modifying the structure of the clinical candidate
plinabulin (<b>1</b>). Although the right-hand imidazole ring
with a branched alkyl chain at the 5-position in <b>1</b> was
critical for the potency of the antimicrotubule activity, we successfully
substituted this moiety with a simpler 2-pyridyl structure by converting
the left-hand ring from a phenyl to a benzophenone structure without
decreasing the potency. The resultant compound <b>6b</b> (KPU-300)
exhibited a potent cytotoxicity, with an IC<sub>50</sub> value of
7.0 nM against HT-29 cells, by strongly binding to tubulin (<i>K</i><sub>d</sub> = 1.3 μM) and inducing microtubule depolymerization
Development of Potent Myostatin Inhibitory Peptides through Hydrophobic Residue-Directed Structural Modification
Myostatin,
a negative regulator of skeletal muscle growth, is a
promising target for treating muscle atrophic disorders. Recently,
we discovered a minimal myostatin inhibitor <b>1</b> (WRQNTRYSRIEAIKIQILSKLRL-amide)
derived from positions 21–43 of the mouse myostatin prodomain.
We previously identified key residues (N-terminal Trp<sup>21</sup>, rodent-specific Tyr<sup>27</sup>, and all aliphatic amino acids)
required for effective inhibition through structure–activity
relationship (SAR) studies based on <b>1</b> and characterized
a 3-fold more potent inhibitor <b>2</b> bearing a 2-naphthyloxyacetyl
group at position 21. Herein, we performed <b>1</b>-based SAR
studies focused on all aliphatic residues and Ala<sup>32</sup>, discovering
that the incorporations of Trp and Ile at positions 32 and 38, respectively,
enhanced the inhibitory activity. Combining these findings with <b>2</b>, a novel peptide <b>3d</b> displayed an IC<sub>50</sub> value of 0.32 μM, which is 11 times more potent than <b>1</b>. The peptide <b>3d</b> would have the potential to
be a promising drug lead to develop better peptidomimetics
Novel Hybrid Compound of a Plinabulin Prodrug with an IgG Binding Peptide for Generating a Tumor Selective Noncovalent-Type Antibody–Drug Conjugate
Although several approaches for making
antibody–drug conjugates
(ADC) have been developed, it has yet to be reported that an antibody
binding peptide such as Z33 from protein A is utilized as the pivotal
unit to generate the noncovalent-type ADC (NC-ADC). Herein we aim
to establish a novel probe for NC-ADC by synthesizing the Z33-conjugated
antitumor agent, plinabulin. Due to the different solubility of two
components, including hydrophobic plinabulin and hydrophilic Z33,
an innovative method with a solid-supported disulfide coupling reagent
is required for the synthesis of the target compounds with prominent
efficiency (29% isolated yield). We demonstrate that the synthesized
hybrid exhibits a binding affinity against the anti-HER2 antibody
(Herceptin) and the anti-CD71 antibody (6E1) (<i>K</i><sub>d</sub> = 46.6 ± 0.5 nM and 4.5 ± 0.56 μM, respectively)
in the surface plasmon resonance (SPR) assay. In the cell-based assays,
the hybrid provides a significant cytotoxicity in the presence of
Herceptin against HER2 overexpressing SKBR-3 cells, but not against
HER2 low-expressing MCF-7 cells. Further, it is noteworthy that the
hybrid in combination with Herceptin induces cytotoxicity against
Herceptin-resistant SKBR-3 (SKBR-3HR) cells. Similar results are obtained
with the 6E1 antibody, suggesting that the synthesized hybrid can
be widely applicable for NC-ADC using the antibody of interest. In
summary, a series of evidence presented here strongly indicate that
NC-ADCs have high potential for the next generation of antitumor agents