Product News | ACS Fall 2023 Debuts Heavyweight R&D Results (2/3)

Sep.27.2023

This summer, the innovative drug industry has been inundated with news.

Last week's American Chemical Society (ACS) 2023 Annual Autumn Meeting in San Francisco, USA, was a great source of inspiration for the innovative drug industry.

TNG-462

(Tango Therapeutics)

TNG-462 is a PRMT5 (Protein Arginine Methyltransferase 5) inhibitor for the treatment of patients with MTAP (Methylthioadenosine Phosphorylase) deficient cancers. 15% of patients with solid tumours, including approximately 15% of NSCLC, 28% of oesophageal cancers, 26% of bladder cancers, and 10% of oesophagogastric cancers, have MTAP deficiency. There is an MTAP deletion, which results in the accumulation of its substrate MTA (methylthioadenosine) and, therefore, higher levels of MTA in certain tumour cells.

PRMT5 is a methyltransferase that uses a universal methyl donor, SAM (S-adenosylmethionine), to methylate substrate proteins.TNG-462 can take advantage of the high levels of MTA in tumour cells and bind to PRMT5 to form the PRMT5-MTA-TNG462 complex, which inactivates PRMT5 and results in a failure to carry out the methylation process in the tumour cells.

TNG462 is on average 45 times more selective for killing MTAP-deficient cells than for normal cells, and its current highest clinical development status is Phase 1/2 for the treatment of locally advanced malignant solid tumours.

STX-478

(Scorpion Theraputic)

PI3Kα (phosphoinositide 3-kinase) is one of the most mutated proteins in cancer, with more than 166,000 cancer patients carrying a mutant form of PI3Kα in the U.S. alone.While Alpelisib, a PI3Kα inhibitor developed by Novartis, has proven to be an effective therapeutic treatment for a variety of cancers in the past, regular PI3Kα inhibition may lead to side effects such as high blood sugar and rash. PI3Kα inhibition can lead to side effects such as hyperglycaemia and skin rashes.

In contrast, STX-478 developed by Scorpion Theraputic has shown good selectivity for H1047X mutant PI3Kα in tumour mouse model experiments and does not interfere with normal metabolism compared to Alpelisib.

In addition, STX-478 has the advantages of being able to cross the blood-brain barrier, low dosage requirement, long half-life and low risk of drug-drug interactions. STX-478 is currently in Phase 2 clinical development and is indicated for the treatment of breast cancer, female genital tumours and squamous cell carcinoma of the head and neck.

JNT-517

(Jnana Theraputic)

Phenylketonuria is caused by a pathogenic variant of the phenylalanine hydroxylase gene. Phenylalanine hydroxylase converts phenylalanine to tyrosine, and a deficiency in phenylalanine hydroxylase leads to a toxic accumulation of phenylalanine in the blood and brain, which triggers the development of psychiatric problems and reduces the patient's quality of life.

SLC6A19 is an important transporter protein responsible for the absorption of neutral amino acids and functions in the gut and kidney. Studies in mouse models have found that deletion of SLC6A19-related genes leads to amino aciduria, which reduces plasma phenylalanine levels by 70%, and therefore the risk of phenylalanine accumulation can be reduced by inhibiting SLC6A19.

Jnana Theraputic, which focuses on metabolite-associated diseases, utilised its cell-based drug discovery platform, RAPID (Reactive Affinity Probe Interaction Discovery), to successfully develop a 'First-In-Class', targeted inhibitor of SLC6A19. JNT-517, a "First-In-Class" phenylketonuria therapeutic drug that targets SLC6A19 inhibition, is currently in Phase 1 clinical studies.

CHK-336

(Chinook Therapeutics)

Primary hyperoxaluria (including PH types 1, 2 and 3) is an autosomal recessive disorder that causes the liver to produce excessive amounts of oxalic acid. These oxalic acids may frequently induce kidney stones, cause chronic kidney disease and even ESRD (end-stage renal disease) in young patients.LDH (lactate dehydrogenase) is the only catalase involved in the final step of hepatic oxalate synthesis, with three subunits, LDHA, LDHB, and LDHC, and thus six tetrameric isoforms exist, of which LDHA serves as a therapeutic target. However, indiscriminate and widespread inhibition of LDHA leads to fatigue and soreness caused by abnormal muscle lactate metabolism.

Chinook Therapeutics has designed a liver-targeted, "First-In-Class" LDHA inhibitor, CHK-336, which effectively reduces urinary oxalate levels to normal in a primary hyperoxaluria type 1 mouse model and demonstrates a favourable safety profile. CHK-336 has been in Phase 1 clinical studies for primary hyperoxaluria, but this study has been suspended.

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