Myostatin, a negative regulator of skeletal muscle growth, is a promising target for treating muscle atrophic disorders. Recently, we discovered a minimal myostatin inhibitor (WRQNTRYSRIEAIKIQILSKLRL-amide) derived from positions 21-43 of the mouse myostatin prodomain. We previously identified key residues (N-terminal Trp, rodent-specific Tyr, and all aliphatic amino acids) required for effective inhibition through structure-activity relationship (SAR) studies based on and characterized a 3-fold more potent inhibitor bearing a 2-naphthyloxyacetyl group at position 21. Herein, we performed -based SAR studies focused on all aliphatic residues and Ala, discovering that the incorporations of Trp and Ile at positions 32 and 38, respectively, enhanced the inhibitory activity. Combining these findings with , a novel peptide displayed an IC value of 0.32 μM, which is 11 times more potent than . The peptide would have the potential to be a promising drug lead to develop better peptidomimetics.

A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 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 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50 value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K d = 1.3 μM) and inducing microtubule depolymerization.

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) (Kd = 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.

Experimental results for methane and carbon dioxide diffusion in coal, as reported in the literature, often lead to diffusion rates of CO2 appearing to be much greater than that of CH4. The interpretation sometimes offered that the diffusion coefficient for CO2 is 1–2 orders of magnitude higher than that of CH4, violates fundamental principles. Nevertheless, the experimental observations require explanation. In this article, we: (a) Develop simplified models for the fast estimation of transport coefficients. These are compared with comprehensive grand canonical Monte Carlo (GCMC) and molecular dynamic (MD) simulations, collectively defined as molecular simulations (MS), which provide theoretical adsorption isotherms and various transport coefficients based on multicenter potential energy equations. The simplified models are shown to have acceptable accuracies. (b) Use the simplified models to compare diffusivities of CO2 and CH4 in carbon nanopores. For all cases examined, the diffusivity of CH4 is always larger than that of CO2. (c) Offer two explanations for the apparently contradictory experimental observations (that CO2 sometimes appears to diffuse much faster than the CH4 molecule, even though CH4 is lighter and has smaller adsorption affinity): (i) CH4 mobility could be significantly reduced by directional forces resulting from irregular pore geometries; and (ii) if pores contain throats with sizes close to the CH4 molecular diameter, the energy barrier that the methane molecules must overcome to proceed through is much larger than that required for CO2. (d) Demonstrate that both mobility and connectivity issues can be addressed using kinetic theory in association with percolation analysis. Furthermore, this method of understanding pore networks provides a number of important quantitative measures including percolation threshold, size of largest cluster, shortest path and tortuosity. Separating different transport mechanisms, as we propose here, provides improved insights into the complex transport phenomena that occur in carbonaceous porous media. In many cases, diffusivities reported in the literature with mixed mechanisms are better named “apparent transport coefficients,” because they lump in other unrelated phenomena, violating the fundamental basis of, or mathematical assumptions imposed on, the definition of diffusion. © 2011 American Institute of Chemical Engineers AIChE J, 2012

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