4 research outputs found
Broadly Applicable and Comprehensive Synthetic Method for <i>N</i>‑Alkyl-Rich Drug-like Cyclic Peptides
We
report a versatile and durable method for synthesizing
highly N-alkylated drug-like cyclic peptides. This
is the first
reported method for synthesizing such peptides in parallel with a
high success rate and acceptable purity that does not require optimizations
for a particular sequence. We set up each reaction condition by overcoming
the following issues: (1) diketopiperazine (DKP) formation, (2) insufficient
peptide bond formation due to the steric hindrance of the N-alkylated amino acid, and (3) instability of highly N-alkylated peptides under acidic conditions. Using this
newly established method, we successfully synthesized thousands of
cyclic peptides to explore the scope of this modality in drug discovery.
We here demonstrate the syntheses of a hundred representative examples,
including our first clinical N-alkyl-rich cyclic
peptide (LUNA18) that inhibits an intracellular tough target (RAS),
in 31% total yield and 97% purity on average after 23 or 24 reaction
steps
Broadly Applicable and Comprehensive Synthetic Method for <i>N</i>‑Alkyl-Rich Drug-like Cyclic Peptides
We
report a versatile and durable method for synthesizing
highly N-alkylated drug-like cyclic peptides. This
is the first
reported method for synthesizing such peptides in parallel with a
high success rate and acceptable purity that does not require optimizations
for a particular sequence. We set up each reaction condition by overcoming
the following issues: (1) diketopiperazine (DKP) formation, (2) insufficient
peptide bond formation due to the steric hindrance of the N-alkylated amino acid, and (3) instability of highly N-alkylated peptides under acidic conditions. Using this
newly established method, we successfully synthesized thousands of
cyclic peptides to explore the scope of this modality in drug discovery.
We here demonstrate the syntheses of a hundred representative examples,
including our first clinical N-alkyl-rich cyclic
peptide (LUNA18) that inhibits an intracellular tough target (RAS),
in 31% total yield and 97% purity on average after 23 or 24 reaction
steps
Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor
Cyclic
peptides as a therapeutic modality are attracting
a lot
of attention due to their potential for oral absorption and accessibility
to intracellular tough targets. Here, starting with a drug-like hit
discovered using an mRNA display library, we describe a chemical optimization
that led to the orally available clinical compound known as LUNA18,
an 11-mer cyclic peptide inhibitor for the intracellular tough target
RAS. The key findings are as follows: (i) two peptide side chains
were identified that each increase RAS affinity over 10-fold; (ii)
physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase
membrane permeability; (iii) restriction of cyclic peptide conformation
works effectively to adjust PCP and improve bio-activity; (iv) cellular
efficacy was observed in peptides with a permeability of around 0.4
× 10–6 cm/s or more in a Caco-2 permeability
assay; and (v) while keeping the cyclic peptide’s main-chain
conformation, we found one example where the RAS protein structure
was changed dramatically through induced-fit to our peptide side chain.
This study demonstrates how the chemical optimization of bio-active
peptides can be achieved without scaffold hopping, much like the processes
for small molecule drug discovery that are guided by Lipinski’s
rule of five. Our approach provides a versatile new strategy for generating
peptide drugs starting from drug-like hits
Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning
Substituting a carbon atom with a
nitrogen atom (nitrogen substitution)
on an aromatic ring in our leads <b>11a</b> and <b>13g</b> by applying nitrogen scanning afforded a set of compounds that improved
not only the solubility but also the metabolic stability. The impact
after nitrogen substitution on interactions between a derivative and
its on- and off-target proteins (Raf/MEK, CYPs, and hERG channel)
was also detected, most of them contributing to weaker interactions.
After identifying the positions that kept inhibitory activity on HCT116
cell growth and Raf/MEK, compound <b>1</b> (CH5126766/RO5126766)
was selected as a clinical compound. A phase I clinical trial is ongoing
for solid cancers