Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol).

Broadly Applicable and Comprehensive Synthetic Method for -Alkyl-Rich Drug-like Cyclic Peptides.

We report a versatile and durable method for synthesizing highly -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 -alkylated amino acid, and (3) instability of highly -alkylated peptides under acidic conditions.

Exploitation of Elevated Extracellular ATP to Specifically Direct Antibody to Tumor Microenvironment.

The extracellular adenosine triphosphate (ATP) concentration is highly elevated in the tumor microenvironment (TME) and remains tightly regulated in normal tissues. Using phage display technology, we establish a method to identify an antibody that can bind to an antigen only in the presence of ATP. Crystallography analysis reveals that ATP bound in between the antibody-antigen interface serves as a switch for antigen binding.

Identification of a selective inhibitor of transforming growth factor β-activated kinase 1 by biosensor-based screening of focused libraries.

Transforming growth factor-β activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, plays an essential role in mediating signals from various pro-inflammatory cytokines and therefore may be a good target for developing anti-inflammation agents. Herein, we report our efforts to identify TAK1 inhibitors with a good selectivity profile with which to initiate medicinal chemistry. Instead of resorting to a high-throughput screening campaign, we performed biosensor-based biophysical screening for a limited number of compounds by taking advantage of existing knowledge on kinase inhibitors.

Development of a Method for Converting a TAK1 Type I Inhibitor into a Type II or c-Helix-Out Inhibitor by Structure-Based Drug Design (SBDD).

We have developed a method for converting a transforming growth factor-β-activated kinase 1 (TAK1) type I inhibitor into a type II or c-helix-out inhibitor by structure-based drug design (SBDD) to achieve an effective strategy for developing these different types of kinase inhibitor in parallel. TAK1 plays a key role in inflammatory and immune signaling, and is therefore considered to be an attractive molecular target for the treatment of human diseases (inflammatory disease, cancer, etc.).

Discovery of a potent and highly selective transforming growth factor β receptor-associated kinase 1 (TAK1) inhibitor by structure based drug design (SBDD).

A novel thienopyrimidinone analog was discovered as a potent and highly selective TAK1 inhibitor using the SBDD approach. TAK1 plays a key role in inflammatory and immune signaling, so TAK1 is considered to be an attractive molecular target for the treatment of human diseases (inflammatory disease, cancer, etc.).

Conformationally restricted analog and biotin-labeled probe based on beauveriolide III.

A conformationally restricted oxazoline analog 7 was designed on the basis of a SAR study of beauveriolide III (2) and its analogs reported previously. Conformational analysis by molecular mechanics calculation suggested that the three side chains of 7 mostly occupy the same spaces as those of 2. The analog 7 was synthesized by peptide coupling of the d-cyclohexylglycine-containing ester 11 and d-Ser-containing dipeptide 12, macrolactamization, and cyclodehydration of 6 for the construction of an oxazoline ring.