Nobel Prize target HIF-2 alpha new drug discovery with patent layout

HIF is the key to induced oxygen concentration changes, and its family members include HIF-1 alpha, HIF-1 beta, HIF-2 alpha, HIF-2 beta, HIF-3 alpha, HIF-3 beta.
HIF consists of two different DNA binding proteins (HIF α and HIF β).
Under normal conditions, HIF alpha is modified by hydroxylation under the action of proline hydroxylase (PHD), and the modified HIF alpha is degraded by ubiquitin, which keeps the high expression level in the cells low.
in low oxygen states, HIF alpha is protected from degradation and binds to specific DNA sequences (HRE) in HIF beta and hypoxic regulatory genes to activate the expression of downstream genes.
hiF-2 alpha activity abnormality is a key carcinogenic driver for cancers such as transparent cellular renal cell carcinoma (ccRCC).
these cancers are characterized by excessive accumulation of HIF-2 alpha proteins, usually due to VHL infestion.
factors that cause VHL inseptification include genetic susceptivity, sorocyte mutations, or methylation.
as a transcription factor, HIF-2 alpha has long been considered unf targetable because most transcription factors lack binding points with small molecule inhibitors.
However, researchers at Southwest Medical Center in Texas have discovered a binding chamber in HIF-2 alpha, which is critical for the realization of functional HIF-2 alpha and HIF-1 beta isopolymer assembly, and the protein interaction may be blocked by small molecule inhibitors.
the binding cavity found in the PAS-B domain of HIF-2 alpha has a space of about 290 s3.
the HIF-2 alpha target in the research drug and molecular structure design highlights mentioned HIF-2 alpha target had to introduce the pioneer company Peleton Therapeutics in this field.
researchers at Southwest Medical Center in Texas obtained the pilot compound of HIF-2 alpha inhibitors after initial screening, and then founded Peroton Therapeutics to further develop HIF-2 alpha inhibitors.
In 2016, Peloton researchers published two articles in Nature and one in Cancer Research, which caused a stir by verifying the effectiveness of the pilot compound PT2399 in preclinical cells and animal models, which is peloton Therapeutics' main contribution to the development of new drugs for HIF-2 alpha targets.
PT2399 Structure Based on the pilot compound PT2399, Peloton Therapeutics uses a structure-based drug design (SBDD) method for molecular structure optimization through the use of assumed color aid group n→π The significant effect of the action to guide the design of early similars, using cocrystalline structure analysis to describe the combination of PT2385 and HIF-2 alpha characteristics, in the PK/PD, efficacy, PK and metabolite spectrometry analysis sequence finally identified PT2385 as a clinical candidate drug, which is the first HIF-2 alpha antagonist into clinical development.
PT2385 completed preliminary safety verification in patients with advanced cCRCC and showed clinical effectiveness.
but the severe effects of glucosal glycoside metabolites limit the dose of PT2385.
Peloton Therapeutics researchers improved the inhibition of HIF-2 alpha activity by changing the double-stranded tefluorocarbon group in PT2385 to adjacent teflonic group, reduced stage 2 metabolism, reduced lipid affinity and significantly improved pharmacodynamic properties of drug molecules, resulting in an exposure dose of PT22977 that significantly improved compared to PT2385.
not only that, but the clinical dose of PT2977 is much lower and is given only once a day.
Table 1 HIF-2 alpha target in the study of drugs Source: Pharmaceutical Rubik's Cube NextPharma Peloton Therapeutics had planned an IPO in May 2019, but just days before the IPO, Mercedon's offer Pyroton's board of directors was moved to pocket the latter with a $1.05 billion down payment and $1.15 billion in mileage, and PT2977 also had a new research and development code, MK-6842.
is currently conducting Phase III clinical trials for the treatment of late-stage RCC (MK-6482-005, NCT04195750).
analysis of the HIF-2 alpha target-related patent analysis by Peleton company HIF-2 alpha target patent, found that PT2385 and PT2977 are basically in the same patent application.
: Same-family patents are selected in the order of CN>US>EP>JP, and if there are multiple authorized patents, they are included in the analysis.
among them: Patent CN105530923B claim 12 protects PT2385, claim 13 protects PT2977, claim 16 protects the application of compounds in the preparation of drugs for the treatment of renal cell carcinoma (RCC); Patent application US2018049995A1 claim 1 claims to protect PT2385 crystalline A, claim 19 claims to protect PT2385 crystalline B; patent application WO2020092100A1 claim 1 requires protection of PT2977 and the formation of oral capsules or tablets; US10278942B2 Claim 14 protects the treatment of pulmonary hypertension (PAH) by HIF-2 alpha inhibitors PT2385, PT2977, and US10512626B2 Claim 14 protects the treatment of glioblastoma with HIF-2 alpha inhibitors PT2385 and PT2977; WO2019191227A1 Claim 43 requires the protection of HIF-2 alpha inhibitors PT2385, PT2977 to reduce inflammation of the digestive system; US10786480B2 Claim 17 protects the combination of HIF-2 alpha inhibitors PT2385, PT2977 and immunotherapy agents for the treatment of non-small cell lung cancer, prostate cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma and breast cancer (claim 22 separately protects the combination of PT2977 and immunotherapy agents to treat cancer).
timeline for patent applications for
5 compounds is as follows: From the first patent from priority date 2013-09-09 to the fifth patent filed in 2016-06-08, Peloton has been looking for the optimal compound structure, from the parent core to the side chain. The structural modification process of
5 compound patents is as follows: The first step is to modify PT2385 to replace the base F atomic position transformation toPT2977;
Conclusion Researchers at Southwest Medical Center in Texas, USA, from the initial discovery of the targeted binding chamber of HIF-2 alpha, to the screening and optimization of pilot structure inhibitors, the establishment of Pelton company and finally the candidate compounds to clinical, complete the clinical proof of effectiveness, is a successful model of clinical transformation of scientific research results.
idea of using structure-based drug design (SBDD) method to modify and improve structure to develop small molecule drugs is recommended.
Peloton's patent application layout for HIF-2 alpha target compound structure is relatively complete, covering the range of mother core, side chain replacement base modification, Mercaton acquired Peloton, target novel, clinical proof of effective, expect to target HIF-The final clinical trial of 2 alpha other structure inhibitors has been successful, bringing novel treatment options to patients with end-line renal cell carcinoma, and it is hoped that the treatment targeting HIF-2 alpha can be pushed to the front line of renal cell carcinoma therapy, maintaining and even improving efficacy and reducing the heart toxic side effects of targeting VEGFR.
references , Yancheng Yu, Quanwei Yu, Xiaojin Zhang, et al., Allosteric resedion of HIF-2 alpha as a novel therapy for clear cell renalcell carcinoma, Discovery Today, Volume 24, Issue 12, December 2019, Pages2332-2340. [2] Rodrigo Almeida Toledo, New HIF2αinhibitors: potential implications as therapeutics foradvancedpheochromocytomas and paragangliomas, Endocrine-Related Cancer (2017)24, C9-C19. [3] Xu R, Wang K, Rizzi JP, et al. 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile(PT2977), a Hypoxia-Inducible Factor 2α(HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma,Journal of Medicinal Chemistry, 2019, 62(15):6876-6893。