Arginase 1/2 Inhibitor OATD-02: From Discovery to First-in-man Setup in Cancer Immunotherapy.

Pharmacologic inhibition of the controlling immunity pathway enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for cancer immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with cancer. SIGNIFICANCE: We have developed an orally available, small-molecule intracellular arginase 1 and 2 inhibitor as a potential enhancer in cancer immunotherapy. Because of its favorable pharmacologic properties shown in nonclinical studies, OATD-02 abolishes tumor immunosuppression induced by both arginases, making it a promising drug candidate entering clinical trials.

Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis.

Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.

Building expanded structures from tetrahedral DNA branching elements, RNA and TMV protein.

By combining both chemical and enzymatic ligation with procedures guiding the self-assembly of nanotubular tobacco mosaic virus (TMV)-like particles (TLPs), novel nucleoprotein structures based on DNA-terminated branching elements, RNA scaffolds and TMV coat protein (CP) are made accessible. Tetrahedral tetrakis(hydroxybiphenyl)adamantane cores with four 5'-phosphorylated dinucleotide arms were coupled to DNA linkers by chemical ligation. The resulting three-dimensional (3D) branching elements were enzymatically ligated to the 3' termini of RNA scaffolds either prior to or after the RNAs' incorporation into TLPs. Thus, architectures with interconnected nanotube domains in two different length classes were generated, each containing 70 CP subunits per 10 nm length. Short TMV origin-of-assembly-containing RNA scaffolds ligated to the DNA allowed the growth of protein-coated 34 nm tubes on the terminal RNA strands in situ. Alternatively, 290 nm pre-fabricated tubes with accessible RNA 3' termini, attained by DNA blocking elements hybridized to the RNAs, were ligated with the branched cores. Both approaches resulted in four-armed nanoobjects, demonstrating a so far unique combination of organic synthesis of branching elements, enzymatic modifications, nucleic acid-based scaffolding and RNA-guided and DNA-controlled assembly of tubular RNA-encapsidating protein domains, yielding a novel class of 3D nucleoprotein architectures with polyvalent protein elements. In the long term, the production route might give rise to supramolecular systems with complex functionalities, installed via the orthogonal coupling of effector molecules to TLP domains.

Phosphoramidate Ligation of Oligonucleotides in Nanoscale Structures.

The folding of long DNA strands into designed nanostructures has evolved into an art. Being based on linear chains only, the resulting nanostructures cannot readily be transformed into covalently linked frameworks. Covalently linking strands in the context of folded DNA structures requires a robust method that avoids sterically demanding reagents or enzymes. Here we report chemical ligation of the 3'-amino termini of oligonucleotides and 5'-phosphorylated partner strands in templated reactions that produce phosphoramidate linkages. These reactions produce inter-nucleotide linkages that are isoelectronic and largely isosteric to phosphodiesters. Ligations were performed at three levels of complexity, including the extension of branched DNA hybrids and the ligation of six scaffold strands in a small origami.