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ACS Highlights: These Molecules Bring New Breakthroughs to Old Targets
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American Chemical Society (ACS) Spring Meeting Highlights: These Molecules Bring New Breakthroughs to Old Targets.
Several biopharmaceutical and technology companies announced the chemical structures of their therapeutic candidates for the first time at the American Chemical Society’s (ACS) Spring 2022 meeting “First-time Disclosures” symposium.
Of the 6 candidate compounds whose chemical structures were announced, 3 targeted cancer targets, and the other drugs were 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 long been concerned by the industry, such as PARP, epidermal growth factor receptor (EGFR), (phosphodiesterase 4) PDE4 and Tau proteins, they Compared with existing therapies, new breakthroughs have been made in different aspects such as mechanism of action, selectivity, and mode of administration.
Drug Candidate: LY3372689
R&D organization: Eli Lilly
Disease area: Alzheimer’s disease
Alzheimer’s disease affects the lives of nearly 40 million people worldwide. The accumulation and spread of neurofibrillary tangles 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. O-GlcNAzyme (OGA) removes the glycosyl group from the tau protein, making it easier to aggregate.
Eli Lilly researchers found that blocking OGA in a mouse model slowed tau protein aggregation by 50 percent.
Through multiple medicinal chemistry optimizations, the scientists generated a candidate compound named LY3372689, which was able to bind to OGA for 14 days at a 1 mg dose and showed a favorable safety profile in early clinical trials. It is currently being evaluated in a Phase 2 clinical trial, with results expected in mid-2024.
Drug Candidate: AZD9574
R&D organization: AstraZeneca
Disease Area: Cancer
The PARP family of proteases plays an important role in the DNA damage response, and existing PARP1 and PARP2 inhibitors have been approved for the treatment of various cancer types harboring DNA damage response defects. At the just-concluded AACR conference, AstraZeneca announced the results of the first human clinical trial of its PARP1 inhibitor AZD5305. It was well tolerated and achieved an objective response rate of 25% in 40 patients evaluable for efficacy.
However, this compound cannot effectively enter the central nervous system. The researchers further optimized AZD5305 by placing the amine group next to the fluorine to generate a PARP1 inhibitor AZD9574 that can enter the central nervous system. In a mouse intracranial tumor xenograft model, it was able to effectively shrink tumors for more than 155 days without showing significant toxicity. The compound is about to enter clinical development.
Drug Candidate: PF-07038124
R&D organization: Pfizer
Target: Phosphodiesterase 4
Disease Area: Inflammatory Skin Diseases
Phosphodiesterase 4 (PDE4) inhibitors are one of the important therapeutic options for the treatment of atopic dermatitis, psoriasis and other inflammatory skin diseases. Blocking PDE4 can slow the body’s inflammatory response, but oral PDE inhibitors are often associated with gastrointestinal side effects.
PF-07038124, developed by Pfizer, is a PDE4 inhibitor intended for topical use. It is designed to be highly effective, rapidly cleared by the body, and have suitable solubility and permeability characteristics for topical formulations.
This candidate therapy has already achieved positive results in a Phase 2a clinical trial for the treatment of atopic dermatitis, significantly reducing disease size and severity in patients at low doses.
▲ The results of the Phase 2a trial of PF-07038124 in the treatment of patients with atopic dermatitis (Image source: Pfizer official website)
With anti-IL-4 and anti-IL-13 antibodies emerging as powerful options for the treatment of inflammatory skin diseases, this topical PDE4 inhibitor offers new opportunities for combination with biologics.
Drug Candidate: BLU-945
Research and development organization: Blueprint Medicines
Target: epidermal growth factor receptor (EGFR)
Disease area: Drug-resistant non-small cell lung cancer
Targeting EGFR is one of the main ways to treat non-small cell lung cancer. Several EGFR inhibitors are already approved to treat non-small cell lung cancer, but most cancers eventually develop resistance to them.
The development of drug resistance is usually due to the accumulation of mutations on EGFR, with T790M and C797S being the most frequently occurring mutations in EGFR after first- and third-generation EGFR inhibitor therapy, respectively.
BLU-945 is an oral fourth-generation EGFR inhibitor that inhibits the activity of EGFR with double or triple mutations.
Preliminary clinical trial results presented at the recently concluded AACR Congress showed that BLU-945 demonstrated a favorable safety profile and a dose-dependent reduction in circulating tumor DNA.
Also, radiographic data showed a dose-dependent shrinkage of the patients’ tumors, with one patient receiving the highest dose of BLU-945 achieving a partial response.
▲BLU-945 dose-dependently reduces circulating tumor DNA (Image source: Blueprint Medicines official website)
Drug Candidate: KVD900
Research and Development Organization: KalVista Pharmaceuticals
Target: Plasma kallikrein
Disease Area: Hereditary Angioedema
Hereditary angioedema (HAE) is a rare and potentially fatal genetic disorder characterized by rapid and painful onset of inflammation of the hands, feet, extremities, face, abdomen, larynx, and airways. Current therapies target plasma kallikreins, which inhibit the release of bradykinin and reduce the inflammatory response.
However, all existing treatments require intravenous or subcutaneous injection, and there is no oral treatment for acute angioedema attacks.
KVD900 is an oral plasma kallikrein inhibitor targeted as acute therapy for the treatment of angioedema episodes in patients with HAE.
In Phase 2 clinical trials, KVD900 significantly advanced the time to symptom relief in patients. It is currently being tested in Phase 3 clinical trials.
Drug Candidate: AMG 650
R&D organization: Amgen
Target: Kinesin family member 18A (KIF18A)
Disease Area: Advanced Solid Tumors
Kinesins are a group of molecular motor proteins that help separate chromosomes. Inhibiting these proteins may cause cell division in tumors to stop.
AMG 650 is a potential “first-in-class” oral KIF18A inhibitor currently being evaluated in a Phase 1 clinical trial for the treatment of solid tumors. Molecular motor proteins are an emerging class of target types. Bristol-Myers Squibb’s mavacameten for cardiomyopathy also targets the molecular motor myosin.
MoMa Therapeutics, which was listed on BioSpace’s 2021 Next-Generation Biotechnologies list last year, is also an emerging company dedicated to the development of molecular motor-targeted therapies.
 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/
 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
ACS Highlights: These Molecules Bring New Breakthroughs to Old Targets
(source:internet, reference only)