noncovalent

Filibuvir (PF-00868554) is a selective and noncovalent inhibitor of HCV NS5B RNA-dependent RNA polymerase. Filibuvir inhibits genotype 1a and 1b replicons with EC50s of 59 nM.

SARS-CoV-2 Mpro-IN-9 (compound c7), a nonpeptidic, noncovalent inhibitor of SARS-CoV-2 main protease (Mpro), exhibits potent inhibitory action (IC50 = 0.085 μM) and improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. It effectively suppresses viral replication in SARS-CoV-2-infected Vero E6 cells (EC50 = 1.10 μM) and demonstrates low cytotoxicity (CC50 > 50 μM) [1].

GRL0617 is a selective and competitive noncovalent inhibitor of SARS-CoVPLpro and deubiquitinase (IC50: 0.6 μM, Ki: 0.49 μM).

CCF0058981 (CCF981) is a 3-chlorophenyl analogue, serving as a noncovalent inhibitor of SARS-CoV-2 3CL pro (SC2), demonstrating potent activity with an IC50 of 68 nM. It also exhibits inhibitory effects against SARS-CoV-1 3CL pro (SC1) with an IC50 of 19 nM, highlighting its antiviral efficacy and potential in COVID-19 research [1].

TBA-7371 (DprE1-IN-1) is a potent inhibitor of DprE1 and PDE6.

Vecabrutinib (SNS-062) is a potent, noncovalent inhibitor of BTK (Kd: 0.3 nM) and ITK (Kd: 2.2 nM), with an IC50 of 24 nM for ITK.

CRM1-IN-2 (Compound KL2) is a noncovalent inhibitor of CRM1, localizing it to the nuclear periphery, reducing its nuclear presence, and inhibiting its nuclear export function. It effectively inhibits the growth of colorectal cancer cells and induces apoptosis [1].

SHR5428 is an orally active, selective, noncovalent inhibitor of CDK7, displaying potent enzymatic inhibition (IC50 = 2.3 nM) and effectively suppressing cellular activity in triple-negative breast cancer MDA-MB-468 cells (IC50 = 6.6 nM) [1].

OATD-02 is an orally active, competitive, reversible, noncovalent inhibitor with slow offset kinetics that targets both Arginase1 and Arginase2, exhibiting inhibitory concentrations (IC50) of 20 nM (hARG1), 39 nM (hARG2), 39 nM (mARG1), and 28 nM (rARG1). Notably, OATD-02 mitigates tumor immunosuppression provoked by these arginases and has potential application in melanoma research [1].

CRM1-IN-3 (B28), a noncovalent inhibitor of CRM1, is utilized in the research of protein localization and tumor studies [1].

NC-R17, an RSL3-based noncovalent GPX4 degrader implicated in ferroptosis, demonstrates anti-tumor activity and is utilized in the design of noncovalent GPX4-targeted proteolysis targeting chimeras (PROTACs) [1].

Praelolide, a potent Nrf2 activator, disrupts Keap1-Nrf2 protein-protein interactions through noncovalent binding to Keap1, inhibiting osteoclastogenesis and the production of reactive oxygen species (ROS). With its potential in osteoclastogenic bone disease research, Praelolide presents a promising avenue for therapeutic exploration.

NRX-0492 is an orally administered compound that efficiently degrades Bruton's tyrosine kinase (BTK) by catalyzing its ubiquitylation and subsequent proteasomal degradation, achieving half-maximal degradation concentrations (DC50) of ≤0.2 nM and 90% degradation concentrations (DC90) of ≤0.5 nM. Additionally, NRX-0492 suppresses B-cell receptor (BCR) signaling, transcriptional activities, and chemokine production by linking a noncovalent BTK-binding domain to Cereblon, an adaptor protein within the E3 ubiquitin ligase complex [1].

Fenebrutinib (GDC-0853) is a selective and noncovalent inhibitor of Bruton’s tyrosine kinase (Btk) with a Ki of 0.91 nM.

GNE-431 is a potent, selective and noncovalent Btk inhibitor with IC50 of 3.2 nM. GNE-431 showed excellent potency against the C481R, T474I, and T474M mutants. GNE-431 may provide a treatment option to patients, especially those who have acquired resistance to ibrutinib by mutation of Cys481 or Thr474.

CRM1-IN-1 (Compound KL1), a noncovalent inhibitor of CRM1, promotes nuclear degradation of CRM1 with an IC50 of 0.27 μM, inhibits CRM1-mediated nuclear export, suppresses cell proliferation, and induces apoptosis in colorectal cancer cells [1].

PF-07059013, an orally active and potent noncovalent modulator of sickled hemoglobin (HbS), specifically binds to Hb with nanomolar affinity and demonstrates substantial partitioning into red blood cells (RBCs), making it useful for sickle cell disease (SCD) research [1][2].

JNJ 10329670 is a highly potent (Ki of approximately 30 nM), nonpeptidic, noncovalent inhibitor of human cathepsin S with immunosuppressive activity.

TDI-8304 is a macrocyclic peptide that acts as a potent, species-selective, and noncovalent inhibitor of Plasmodium falciparum (Pf20S). It demonstrates high selectivity for Pf20S compared to human proteasomes [1].

ML188 is a selective noncovalent SARS-CoV 3CLpro inhibitor(IC50 : 1.5 μM), with moderate MW and good enzyme and antiviral inhibitory activity.