Recently, GeninTech, a subsidiary of pharmaceutical giant Roche, and Jiyu Small Molecule Innovation Research Institute, a subsidiary of Jimin Trust, signed an exclusive licensing agreement to buy a prostate cancer targeted androgen receptor (AR) protein degradation (TPD) drug for up to $650 million: "JMKX002992"
Through this licensing agreement, Roche added a new drug
Prostate cancer is an important cause of cancer death in
Androgen receptor (AR) transcription factors are the main regulators of normal glandular homeostasis of the prostate gland and the growth and survival of prostate cancer cells
The androgen receptor AR is a transcription protein, and dysregulation of transcription factors is associated with a variety of diseases
Traditional small molecule drugs for AR on the market include Janssen's AR inhibitor Erleada (apalutamide), Pfizer's AR inhibitor Xtandi (enzalutamide), Bayer's AR inhibitor Nubeqa (darolutamide), etc
However, these proteins have traditionally been considered challenging drug targets
Protein degraders represented by PROTAC have shown great potential over the past few years, with the ability to overcome drug resistance and target previously incurable proteins
In 2001, the Deshaies Lab at the California Institute of Technology and the Cruise Lab at Yale University published their seminal paper formalizing the concept
ARV-110 (bavdegalutamide) is the fastest-growing PROTAC candidate for Arvinas' degradation of AR proteins for the treatment of prostate cancer
In preclinical studies, ARV-766 degraded all AR resistance driver point mutations, including L702H, a mutation associated with abiraterone and other targeted AR pathway therapy treatments, while ARV110 (bavdegalutamide) was not degraded in preclinical studies
It is worth mentioning that ARV-766, which has the same name as the AR degrader, is actually a negative control compound
Note: This result should not be true of the ARV-766 structure that is currently in Phase I clinical trials
Recently, the academic community has also made continuous breakthroughs in the development of degradants for targeting AR:
In September 2021, the team of Professor Shaomeng Wang of Medicinal Chemistry at the University of Michigan reported the PROTAC oral degrader ARD-2585, which is designed
In addition, in mouse experiments, it exhibited 51% oral bioavailability and outperformed enzalutamide in inhibiting the growth of tumor models, and no toxicity
In 2022, Professor Wang Shaomeng introduced the development of AR degraders by martial arts masters in the pharmaceutical industry in JMC Review, and early scientists at Takeda in Japan used IAP ligands to design bifunctional degraders, which they named apoptosis protein-dependent protein erasurers (SNIPERs
Compounds 135 to 137, by prof.
Crews, founder of PROTAC, achieved a degradation potency
of less than nanomolars in prostate cancer-related cell experiments such as VCaP, LNCaP, and 22RV1.
But despite their excellent degradability, compounds 136 and 137 have low oral bioavailability in animals, limiting their further development
.
ARV110 is the culmination of AR degraders, which consists of potent inhibitors, CRBN ligand fluorine-containing derivatives connected by rigid connecters, has excellent AR degradation potency, prostate cancer cell inhibitory activity, good oral druggability and has shown anti-tumor efficacy
in animal experiments.
Over the past half-century, pharmaceutical companies and academic research labs have invested a lot of effort in developing androgen receptor drugs, including FDA-approved androgen receptor agonists, and inhibitors
.
The second-generation AR inhibitors enzalutamide, apalutamide and darolutamide are clinically selective, potent, effective and have fewer
side effects.
However, the rapid emergence of resistance to these drugs means that new strategies for drug development targeting androgen receptors are needed
.
Different from traditional small molecule drugs, the advantage of targeted protein degraders (TPD) drugs represented by molecular gums and PROTAC is to reduce the side effects caused by off-target drugs of traditional small molecule drugs, and can also overcome the resistance caused by the increased expression and mutation of inhibitor drugs, as well as the characteristics of catalysts, which can be reused, and 1 TPD molecule can repeatedly degrade the pathogenic target protein
.
However, at present, PROTAC compounds are facing the problem
of excessive molecular weight and poor drug-ready properties.
This means that oral administration requires an increase in dose, creating potential toxic side effects
.
In addition, not all proteins can be efficiently degraded, such as BRD4 has potential on-target side effects, and IRAK4 inhibitors and degraders have encountered some difficulties
.
Although there is no FDA-approved drug at present, after more than 20 years of technical accumulation, PROTAC will eventually usher in its era
.
Recently, GeninTech, a subsidiary of pharmaceutical giant Roche, and Jiyu Small Molecule Innovation Research Institute, a subsidiary of Jimin Trust, signed an exclusive licensing agreement to buy a prostate cancer targeted androgen receptor (AR) protein degradation (TPD) drug for up to $650 million: "JMKX002992"
.
Through this licensing agreement, Roche added a new drug
in the field of prostate cancer that targets a degrading agent of transcription protein AR.
Last month, Roche halted the Phase 1 clinical trial
of the AKT inhibitor ipatasertib for prostate cancer.
Prostate cancer is an important cause of cancer death in
men.
According to WHO statistics, there will be 1.
41 million new cases of prostate cancer in the world in 2021, the incidence rate is second only to breast cancer, lung cancer and colorectal cancer, ranking 4th, and has become the most common "male health killer"
.
Androgen receptor (AR) transcription factors are the main regulators of normal glandular homeostasis of the prostate gland and the growth and survival of prostate cancer cells
.
Therefore, AR-targeted therapy can be effective in improving the overall survival of
patients with advanced prostate cancer that cannot be cured by surgery or radiation therapy.
The androgen receptor AR is a transcription protein, and dysregulation of transcription factors is associated with a variety of diseases
.
And p53, Myc, NF-kappaB and other proteins are also transcription factors of the androgen receptor AR has been the main target of prostate cancer, many companies have developed targeted AR drugs
.
Traditional small molecule drugs for AR on the market include Janssen's AR inhibitor Erleada (apalutamide), Pfizer's AR inhibitor Xtandi (enzalutamide), Bayer's AR inhibitor Nubeqa (darolutamide), etc
.
However, these proteins have traditionally been considered challenging drug targets
.
In addition, resistance to traditional inhibitors also hinders the clinical application
of these drugs.
Protein degraders represented by PROTAC have shown great potential over the past few years, with the ability to overcome drug resistance and target previously incurable proteins
.
In 2001, the Deshaies Lab at the California Institute of Technology and the Cruise Lab at Yale University published their seminal paper formalizing the concept
of proteolytically targeted chimeras (PROTACs).
ProTAC, which targets AR, enters clinical trials
20 years later.
ARV-110 (bavdegalutamide) is the fastest-growing PROTAC candidate for Arvinas' degradation of AR proteins for the treatment of prostate cancer
.
It is currently in the clinical phase 2 stage
.
Avinas also has an oral PROTAC drug, ARV-766, in phase I clinical trials
.
The structure of the compound of ARV-766 entering the Phase I clinic has not yet been made public, but it is easily confused with
the BDR4 degrader published in Professor Crews' paper in 2016.
According to the Official Website of Avinas, they are developing ARV-766, an oral PROTAC protein degrader for AR for the treatment of men
with mCRPC.
In preclinical studies, ARV-766 degraded all AR resistance driver point mutations, including L702H, a mutation associated with abiraterone and other targeted AR pathway therapy treatments, while ARV110 (bavdegalutamide) was not degraded in preclinical studies
.
It is worth mentioning that ARV-766, which has the same name as the AR degrader, is actually a negative control compound
of the BRD4 degrader ARV771.
Some toxic side effects
were observed during the development of the BRD4 inhibitor ARV-771.
Raina et al.
, observed various toxic side effects during the use of ARV-771 (drug No.
76), including skin discoloration at the injection site, although skin color will return
after 2-3 days of medication.
Another more worrying effect was that the mice could not tolerate the daily doses, had to be administered intermittently every other day, and also observed a decrease in activity levels and spinal deformities
in the mice.
The mechanism of these associated toxicities is unclear, but may not be due to protac-specific side effects
.
Because in RNAi mouse models, inhibition of BRD4 has been shown to cause reversible epidermal hyperplasia and hair loss, but overall, protac's benefit-to-risk ratio is still good
.
Note: This result should not be true of the ARV-766 structure that is currently in Phase I clinical trials
.
The structure in the article is BASED ON THE PROTAC OF THE BRD4 inhibitor JQ1, originally from a 2016 article by Professor Crews (10.
1073/pnas.
1521738113), in which this compound is inactive
.
Because the E3 end is connected to VHL, the cis- and trans- isomers of VHL lead to the presence or absence of activity, which is particularly suitable for PROTAC-negative controls
.
cis-hydroxyprolines cannot be combined with E3 ligase, trans-hyp can be combined with E3 ligase
.
At present, the structure of clinical ARV766 is still uncertain, and it may be code-named multiplexing
.
The structure in the figure may be the structure of the BRD4 degrader in the old text
.
Recently, the academic community has also made continuous breakthroughs in the development of degradants for targeting AR:
In September 2021, the team of Professor Shaomeng Wang of Medicinal Chemistry at the University of Michigan reported the PROTAC oral degrader ARD-2585, which is designed
for degrading AR.
There is excellent protein degradation activity with a DC50 of less than 0.
1 nM
.
Ic50 values in the two cell lines associated with prostate cancer, VCaP and LNCaP, were 1.
5 nM and 16.
2 nM
, respectively.
In addition, in mouse experiments, it exhibited 51% oral bioavailability and outperformed enzalutamide in inhibiting the growth of tumor models, and no toxicity
was observed.
In 2022, Professor Wang Shaomeng introduced the development of AR degraders by martial arts masters in the pharmaceutical industry in JMC Review, and early scientists at Takeda in Japan used IAP ligands to design bifunctional degraders, which they named apoptosis protein-dependent protein erasurers (SNIPERs
).
Compound 132 is one such SNIPER molecule
.
VCaP cell inhibitory activity IC50 values reach 1 μM
.
Compounds 135 to 137, by prof.
Crews, founder of PROTAC, achieved a degradation potency
of less than nanomolars in prostate cancer-related cell experiments such as VCaP, LNCaP, and 22RV1.
But despite their excellent degradability, compounds 136 and 137 have low oral bioavailability in animals, limiting their further development
.
ARV110 is the culmination of AR degraders, which consists of potent inhibitors, CRBN ligand fluorine-containing derivatives connected by rigid connecters, has excellent AR degradation potency, prostate cancer cell inhibitory activity, good oral druggability and has shown anti-tumor efficacy
in animal experiments.
Over the past half-century, pharmaceutical companies and academic research labs have invested a lot of effort in developing androgen receptor drugs, including FDA-approved androgen receptor agonists, and inhibitors
.
The second-generation AR inhibitors enzalutamide, apalutamide and darolutamide are clinically selective, potent, effective and have fewer
side effects.
However, the rapid emergence of resistance to these drugs means that new strategies for drug development targeting androgen receptors are needed
.
Different from traditional small molecule drugs, the advantage of targeted protein degraders (TPD) drugs represented by molecular gums and PROTAC is to reduce the side effects caused by off-target drugs of traditional small molecule drugs, and can also overcome the resistance caused by the increased expression and mutation of inhibitor drugs, as well as the characteristics of catalysts, which can be reused, and 1 TPD molecule can repeatedly degrade the pathogenic target protein
.
However, at present, PROTAC compounds are facing the problem
of excessive molecular weight and poor drug-ready properties.
This means that oral administration requires an increase in dose, creating potential toxic side effects
.
In addition, not all proteins can be efficiently degraded, such as BRD4 has potential on-target side effects, and IRAK4 inhibitors and degraders have encountered some difficulties
.
Although there is no FDA-approved drug at present, after more than 20 years of technical accumulation, PROTAC will eventually usher in its era
.
