Azaindoles as Zinc-Binding Small-Molecule Inhibitors of the JAMM Protease CSN5

Cullin-RING ligases (CRLs) represent the largest family of E3 ubiquitin ligases. CSN5 is the zinc metalloprotease subunit of the COP9 signalosome, an important regulator of CRLs. Elevated expression of CSN5 has been found in several types of cancers. Altmann and coworkers describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion through an unprecedented binding mode. Nanomolar inhibitors led to degradation of the substrate recognition subunit Skp2 and reduced the viability of HCT116 cells. The study provides a proof-of-concept for the potential of CSN5 inhibitors as anticancer agents

Azaindoles as zinc-binding small molecule inhibitors of the JAMM protease CSN5

The COP9 signalosome (CSN) is an eight-subunit protein complex which is an important regulator of Cullin-Ring E3 ubiquitin ligases (CRLs). CSN5 is the Zinc metalloprotease subunit of CSN and is responsible for the cleavage of the ubiquitin-like protein NEDD8 from CRLs. Blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state leading to their inactivation by inducing auto-ubiquitination and subsequent degradation. Consequently CRL substrates (e.g. tumor suppressors p27 and p21) are stabilized resulting in inhibition of cell proliferation. Thus pharmacological inhibition of CSN5 has the potential to offer a new therapeutic strategy for an efficacious treatment of CSN5 dependent cancers. A high-throughput screen (HTS) with the entire CSN complex led to the identification of an azaindole hit as a micromolar CSN5 inhibitor. Optimization of this hit resulted in a series of potent CSN5 inhibitors which stabilized neddylated Cullin-1 and led to the degradation of Skp2 in HCT116 cells. Furthermore these inhibitors demonstrated the expected functional effect on inhibiting viability of cancer cells. In addition a X-ray cocrystal structure elucidated the binding mode and revealed the N7 of the azaindole as a monodate ligand of the active site Zn2+ ion. The 7-azaindole motif represents a novel Zinc-binding scaffold for metalloproteases

Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor XIa inhibitors: Demonstrating the power of an integrated S1 protease family approach

The serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients

Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach

The serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients