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WHO Inventory | Ten Most Potential Small Molecules
In early August, the World Health Organization (WHO) updated the drug inventory for the second quarter. As is well known, drug research and development is a long cycle, which involves 3 to 5 years of clinical in vitro and in vivo experimental screening from thousands of candidate molecules, and ultimately few can advance clinical research. The smooth advancement of the clinical stage is an important milestone for drugs to obtain approval and enter the market.
In this article, MCE will combine public information to present a list of ten small molecule drugs that have quickly entered clinical trials.
Irpagratinib (ABSK011) is a novel and highly selective small molecule FGFR4 inhibitor.
In preclinical studies, the target protein IC50 of ABSK-011 was < 10 nM, with at least 50 times selectivity compared to other FGFR kinases. Oral administration of ABSK-011 strongly inhibits the growth of subcutaneous xenograft tumors and induces FGFR4 activity dependent regression[1].
Fig 1. Mechanism of action of ABSK011.
Public information indicates that ABSK-011 is undergoing a phase 2 clinical study aimed at evaluating its safety and tolerability in combination with Atilizumab in patients with advanced or unresectable HCC[2].
In addition, a phase 1 clinical trial of ABSK-011 as a monotherapy for advanced HCC patients was conducted simultaneously, mainly to evaluate the recommended extended dose (RDE) and safety of oral ABSK-011[2].
Vorbipiprant (CR6086) is a novel, effective, selective, and oral small molecule prostaglandin EP4 receptor antagonist with immunomodulatory properties.
Fig 2. The mechanism of action of EP4 receptor antagonist[3].
Public information indicates that a phase 1/2 clinical trial of CR6086 combined with Balstilimab (AGEN2034) for the treatment of refractory metastatic colorectal cancer is currently underway.
In addition, a phase 2 trial is being conducted to evaluate the efficacy, safety, and pharmacokinetics of oral CR6086 in combination with Methotrexate at doses of 30, 90, or 180 mg in the treatment of rheumatoid arthritis patients[4].
Glecirasib (JAB-21822) is a potent and irreversible KRAS G12C inhibitor that covalently binds to the cysteine residue mutated at position 12 of KRAS G12C, locking KRAS G12C in an inactive state, thereby blocking KRAS dependent signal transduction, inhibiting tumor cell proliferation, and inducing cell apoptosis. Glecirasib is a potential 'Best-in-class' molecule[5].
Fig 3. The Mechanism of KRAS G12C Inhibitors.
Public information indicates that JAB-21822 is conducting a phase 1/2 trial for KRAS p.G12c mutation in advanced solid tumors, aimed at evaluating safety, tolerance, pharmacokinetics, and anti-tumor activity.
In addition, JAB-21822 has also conducted multiple phase 1/2 clinical trials for indications such as non-small cell lung cancer, advanced colorectal cancer, appendix cancer, and pancreatic ductal cancer[6].
Bocodepsin (OKI-179) is a novel oral bioavailable class I selective HDAC inhibitor. OKI-179 exhibits anti-tumor activity in preclinical cancer models, with good pharmacokinetic characteristics and targeted pharmacological effects[7][8].
Fig 4. The anti-tumor mechanism of HDAC inhibitors[7].
According to publicly available information, a phase 1/2 study is underway on OKI-179 combined with Binimetinib for the treatment of late stage solid tumor patients with RAS pathway activation mutations and late stage NRAS mutant melanoma patients, aiming to explore the optimal dosage of OKI-179.
In addition, a phase 1 study of OKI-179 as a single drug for the treatment of advanced solid tumor patients has been completed[9].
Lixumistat (IM156) is a protein complex 1 (PC1) inhibitor that targets the oxidative phosphorylation (OxPhos) pathway in mitochondria and reduces abnormal cell growth in target cancer cells and fibrosis[10][11].
Fig 5. Mechanism of OxPhos inhibitor action[10].
It is reported that the first human trial of Lixumustt (IM156) was conducted at M.D. Anderson Cancer Center to evaluate the therapeutic effect of IM156 combined with Gemcitabine and albumin bound paclitaxel on pancreatic cancer patients[12].
In addition, a phase 1 clinical study of IM156 as a single drug for patients with advanced solid tumors and lymphoma has been completed, aiming to evaluate safety, tolerance, and initial efficacy[12].
Frunexian (EP-7041) has high selectivity towards the target, with an IC 50 of 7.1 nM inhibiting human FXIa. Preclinical in vivo studies have shown that EP-7041 can inhibit thrombosis while minimizing unnecessary bleeding risks[13].
Mosnodenvir (JNJ-1802) is a direct antiviral small molecule of pan serum type dengue fever, which has in vitro potency from picomol to nanomolar pan serum type and has shown in vivo potency in mouse and non human primate models[15].
Fig 7. Mechanism of JNJ-1802.
According to literature reports, the main objectives of the first human study of JNJ-1802 include investigating the safety and tolerability of JNJ-1802 in healthy participants after single or multiple oral doses under fasting conditions. The secondary research objective is to investigate the pharmacokinetics (PK) of JNJ-1802 in healthy subjects after single and multiple oral doses under fasting conditions[15].
Malaria is caused by protozoan parasites of the genus Plasmodium, with high mortality and incidence rate. Sutidiazine (Zy-19489) is a novel triaminopyrimidine antimalarial candidate drug[16][17].
Fig 8. Malaria parasite life cycle[16].
It is reported that Zy-19489 is administered orally and a Phase 1 clinical trial has been completed to study the safety, tolerability, and pharmacokinetics of healthy adult subjects[18].
In addition, a phase 1 clinical trial is currently underway for the combination of Ferroquine (FQ) administration in asymptomatic adult carriers of Plasmodium falciparum[18].
Perfluorohexyloctane (NOV03；SHR8058) is a research-oriented, novel, single entity, anhydrous, and preservative-free eye drop composed of 100% perfluorohexane, which can quickly diffuse on the surface of the eye and form a stable locking layer[19][20][21].
Fig 9. Schematic diagram of eye surface and tear film[19].
Bemfivastatin (PPD 10558), as a lipid-lowering 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor with oral activity, is a statin drug that enhances liver extraction function and is being developed for the treatment of hypercholesterolemic myalgia in patients who are unable to tolerate statins due to their association with statins[22][23].
Fig 10. The lipid-lowering mechanism of HMG-CoA reductase inhibitors[22].
Public information indicates that PPD 10558 is undergoing a double-blind, randomized, placebo-controlled, and actively controlled phase 2b clinical study to evaluate its association with atorvastatin in the incidence of statin related myalgia, lipid effects, safety, and tolerability in primary hypercholesterolemia Fredrickson IIa or IIb patients[24].
Vorbipiprant (CR6086) is an EP4 receptor antagonist, serving as a targeted immunomodulator. Thus, Vorbipiprant is also a potential immune checkpoint inhibitor, to turn cold tumors into hot tumors.
![Fig 4. The anti-tumor mechanism of HDAC inhibitors [7].](/get-image.html?q=news/2023-10/who-20231008-4.jpg)
![Fig 5. Mechanism of OxPhos inhibitor action [10].](/get-image.html?q=news/2023-10/who-20231008-5.jpg)
