▎ WuXi AppTec content team editor
Recently, at the "First-time Disclosures" symposium of the American Chemical Society's (ACS) spring 2022 meeting, a number of biomedical and technology companies announced the chemical structure of the proposed therapies under development for the first time. Of the 6 candidate compounds with published chemical structures, 3 target cancer targets, and other drugs are used to treat Alzheimer's disease, inflammatory skin diseases, and hereditary angioedema. Although many of these new molecules target disease-related targets or mechanisms that have been concerned by the industry for a long time, such as PARP, epidermal growth factor receptor (EGFR), (phosphodiesterase 4), PDE4 and Tau protein, they have made new breakthroughs in different aspects of mechanism of action, selectivity, and mode of administration compared with existing therapies. In today's article, WuXi AppTec's content team will combine reports from the drughunter.com and ACS's C&EN website to share with readers these newly announced molecular structure candidates.
Image credit: 123RF
Drug candidate: LY3372689
R&D organization: Eli Lilly
Target: O-GlcNA enzyme
Disease field: Alzheimer's disease
Image source: References[1]
Alzheimer's disease affects the lives of nearly 40 million people worldwide. The accumulation and spread of neurofiber entanglements composed of Tau protein in the patient's brain is one of the hallmark features of the patient's brain and is closely related to the patient's cognitive decline. The O-GlcNA enzyme (OGA) removes the glycosyl groups from the Tau protein, making it easier to aggregate.
Eli Lilly researchers found that blocking OGA in mouse models delayed Tau protein aggregation by 50 percent. Through a variety of pharmaceutical chemical optimizations, the scientists generated a candidate compound called LY3372689, which was able to bind to OGA for 14 days at a dose of 1 mg, showing good safety in early clinical trials. It is currently being evaluated in a Phase 2 clinical trial and the results are expected to be available in 2024.
Drug Candidate: AZD9574
R&D organization: AstraZeneca
Target: PARP1
Disease field: Cancer
Image source: References[1]
The PARP family of proteases plays an important role in DNA damage reactions, and existing PARP1 and PARP2 inhibitors have been approved to treat cancer types that carry multiple DNA damage response defects. At the just-concluded AACR conference, AstraZeneca announced the results of its first human clinical trial of its PARP1 inhibitor AZD5305. It showed good tolerability and achieved an objective response rate of 25% in 40 patients who could assess efficacy.
However, this compound can not effectively enter the central nervous system, the researchers further optimized AZD5305, by placing the amine group next to fluorine, the parp1 inhibitor AZD9574 can enter the central nervous system. In a mouse intracranial tumor transplant model, it was able to effectively shrink tumors for more than 155 days and did not exhibit significant toxicity. This compound is about to enter the clinical development phase.
R&D institution: Pfizer
Target: Phosphodiesterase 4
Disease field: inflammatory skin diseases
Image source: References[1]
In the case of anti-IL-4 and anti-IL-13 antibodies becoming a powerful choice for the treatment of inflammatory skin diseases, this topical PDE4 inhibitor offers new opportunities for combination with biological products.
Drug candidate: BLU-945
R&D organization: Blueprint Medicines
Target: Epidermal Growth Factor Receptor (EGFR)
Disease area: Drug-resistant non-small cell lung cancer
Image source: References[1]
Targeting EGFR is one of the main ways to treat non-small cell lung cancer. Several EGFR inhibitors have been approved to treat non-small cell lung cancer, but most cancers will eventually become resistant to them. Usually resistance arises due to the accumulation of mutations on EGFR, T790M and C797S, which are most commonly seen after treatment with first- and third-generation EGFR inhibitors, respectively.
BLU-945 is an oral fourth-generation EGFR inhibitor that inhibits EGFR activity carrying double or triple mutations. Zaiding Pharmaceutical owns the development interest in this EGFR inhibitor in Greater China. Preliminary clinical trial results presented at the recently concluded AACR conference showed that BLU-945 showed good safety and reduced dose dependence in circulating tumor DNA. Moreover, radiographic data showed a dose-dependent reduction in the patients' tumors, with one patient receiving the highest dose of BRU-945 achieving a partial response.
▲BLU-945 dose-dependent reduction circulating tumor DNA (Image source: Blueprint Medicines official website)
Drug candidate: KVD900
R&D organization: KalVista Pharmaceuticals
Target: Plasma kallikrein
Area of the disease: Hereditary angioedema
Image source: References[1]
Hereditary angioedema (HAE) is a rare potentially fatal genetic disorder characterized by rapid and painful onset of disease with inflammation of the hands, feet, limbs, face, abdomen, larynx, and trachea. Current therapies target plasma kallikreins, which can inhibit the release of bradykinin and reduce the inflammatory response. However, existing therapies require intravenous or subcutaneous injections, and there is no oral therapy that can target the onset of acute angioedema.
KVD900 is an oral plasma kallikrein inhibitor that aims to treat episodes of angioedema in patients with HAE as an acute therapy. In a Phase 2 clinical trial, KVD900 significantly preceded the time when patients experienced remission of symptoms. It is currently being tested in a Phase 3 clinical trial.
Drug candidate: AMG 650
R&D institution: Amgen
Target: Kinin Family Member 18A (KIF18A)
Disease area: Advanced solid tumor
Image source: References[1]
Kinesins are groups of molecular motor proteins that help complete the separation of chromosomes. Inhibition of these proteins may cause cell division in the tumor to stop.
AMG 650 is a potential "first-in-class" oral KIF18A inhibitor that is currently being evaluated in Phase 1 clinical trials for the treatment of solid tumors. Molecular motor proteins are an emerging class of target types. Bristol-Myers Squibb's mavacameten, which is used to treat cardiomyopathy, is also targeting the molecule motor myosin. MoMa Therapeutics, which was named on BioSpace's list of next-generation bio-cutting companies of the year 2021 last year, is also a cutting-edge company dedicated to the development of molecular motor-targeted therapies.
I wish that the research and development of these research and development therapies will proceed smoothly and become innovative therapies that will change the lives of patients as soon as possible.
Resources:
[1] In Context: First-Time Disclosures of ACS Spring 2022. Retrieved April 13, 2022, from https://drughunter.com/in-context-first-time-disclosures-of-acs-spring-2022/
[2] Hybrid meeting divulges structures of drug candidates. Retrieved April 13, 2022, from https://cen.acs.org/acs-news/acs-meeting-news/Hybrid-meeting-divulges-structures-drug-candidates/100/web/2022/03
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