Newsletter Signup – Under Article / In Page
“*” indicates required fields
You may already be familiar with protein degraders, drugs designed to eliminate disease-causing proteins, which have shown promising activity as cancer therapies. But have you heard of Regulated Induced Proximity Targeted Chimeras (RIPTACs), a new protein technology that targets tumor cells? Halda Therapeutics has now brought the first-ever RIPTAC into clinical trials, aiming to advance the next generation of induced proximity therapies.
In this article, we’ll explore what RIPTACs are, how they differ from existing protein degraders, and why Halda Therapeutics’ clinical milestone matters.
How do RIPTACs work?
RIPTACs are bifunctional small molecules designed to selectively target tumor cells by bringing together two distinct proteins: one that is highly expressed in tumor cells and another that is essential for cellular survival. Each RIPTAC consists of two ligands connected by a linker – one ligand binds specifically to a tumor-associated protein, while the other binds to a protein critical for cell viability. By physically linking these two proteins, RIPTACs can precisely disrupt essential cellular functions, leading to the targeted elimination of tumor cells.
This setup may remind you of antibody-drug conjugates (ADCs), which are composed of a monoclonal antibody, a cytotoxic drug – typically a chemotherapy – and a linker. But unlike ADCs, which deliver the drug specifically to the tumor as the monoclonal antibody binds to a specific target protein on the surface of cancer cells, RIPTACs create a neo-protein-protein interaction surface in a stable complex.
Christian Schade, chief executive officer (CEO) of American biotech Halda Therapeutics, explained that by doing so, it leads to tumor-specific cell death.
“The RIPTAC is highly selective and highly potent, akin to an ADC, but in a small molecule, oral format,” said Schade.
HLD-0915: Halda Therapeutics’ revolutionary approach to targeting cancer
Invented by Halda Therapeutics, HLD-0915 is the investigational drug that has just set foot into the clinic. It is a RIPTAC that binds to the androgen receptor (AR) – highly expressed in prostate cancer cells – and to an undisclosed protein that is essential for cell function, explained Schade. The drug is designed to drive specific interactions between these two proteins to achieve optimal activity and pharmacology through what Halda calls the “hold and kill” mechanism.
This has been illustrated in preclinical studies where HLD-0915 exhibited tumor shrinkage and the decline of circulating prostate-specific antigen (PSA) – a protein produced by the prostate gland and a tool in prostate cancer screening – in models including ones of drug resistance, “while delivering a favorable therapeutic index.”
“We are excited to share data demonstrating the mechanism of action of RIPTAC molecules, as well as how the protein proximity paradigm can be extended into direct cancer cell killing,” said Kanak Raina, lead author of the preclinical study and head of Biology at Halda, in a press release. “Insights gained from the detailed interrogation of this chemical biology model have provided Halda with a robust foundation that has resulted in our pipeline of RIPTAC therapeutics for major cancers.”
Can RIPTACs tackle unmet needs of patients with prostate cancer?
This is a step forward in prostate cancer research. The typical oral drugs for people with prostate cancer target the AR signaling pathway, like RIPTACs. However, tumor cells adapt to these agents through a myriad of mechanisms, and resistance occurs through AR-dependent signaling – caused by splice variants such as AR-V7, a key driver of resistance to these therapies – and even independent cell signaling, Schade pointed out. This poses a significant challenge in prostate cancer care since treatments may eventually lose effectiveness. As this unmet need stands out, RIPTACs are designed to get around the issue of drug resistance.
“Unlike other oral modalities, RIPTACs only need the presence of AR in the tumor cell but do not rely on AR being the disease driver. As a result, HLD-0915 is expected to have broad activity in this large patient population,” said Schade.
Moreover, Halda’s RIPTAC HLD-0915 is an oral therapy. This minimizes the difficulties of having to get frequent intravenous injections at the hospital.
“Patients can take home a bottle of pills as opposed to having to go into the clinic to get intensive weekly infusions. Other intravenous agents that may be options have tremendous complexities of manufacturing and patient access, none of which are an issue with HLD-0915,” expressed Schade.
Therapies such as radiopharmaceuticals, ADCs, and T-cell engagers deploy a molecule to engage a cancer cell and ultimately, selectively cause its death. While they are ”designed to offer similar benefits,” “only RIPTACs offer the convenience and simplicity of an oral drug agent,” expressed Schade.
To add to that, these other therapies rely on engaging cancer cells “extracellularly.” According to a research paper published in the journal Cell Chemical Biology, they are unable to take advantage of most cancer-selective proteins, making it a less targeted approach.
“HLD-0915 is a significant step towards an oral, small molecule therapy that overcomes the multitude of resistance mechanisms that arise in response to other drugs,” said Schade. “Prostate cancer is treated first and foremost in the community setting, and a broadly effective oral drug fits with this treatment setting, in contrast to injectable medicines that require complex care and medical monitoring.”
How similar are RIPTACs to PROTACs?
Before RIPTACs appeared on the scene, protein degraders called proteolysis-targeting chimeras, familiarly known as PROTACs, have been studied for more than two decades. They are a type of small molecule that promotes the degradation of specific proteins by recruiting the cellular ubiquitin-proteasome system (UPS) to target proteins for destruction. While a PROTAC is yet to be approved by the U.S. Food and Drug Administration (FDA), there are a few in the clinic, like Arvinas’ vepdegestrant and C4 Therapeutics’ cemsidomide.
Motivated by the success of molecular glues and PROTACs, RIPTACs could pave the way beyond traditional protein degraders, according to a report in the National Library of Medicine. But just because they’re both bifunctional molecules, they don’t work the same way.
“RIPTACs operate via an entirely different mechanism of action compared to degraders,” said Schade. “Degraders can be effective if full-length AR is driving the tumor growth but become less effective when independent resistance mechanisms arise, especially upon progression on approved agents.”
While RIPTACs leverage tumor-specific AR expression to act selectively on cancer cells, they do not target its activity.
“As a result, they are effective even in AR-independent settings. Similarly, because clinical degraders do not target AR splice variants, like AR-V7, they are ineffective in tumors driven by this mechanism. However, because AR-V7 expression in tumor cells occurs alongside full-length AR, RIPTACs can still kill the tumor cell by leveraging this full-length AR expression to form a trimer complex with the essential protein.”
Bifunctional therapies: a young but diverse therapeutic field
Although RIPTACs are a creation of Halda Therapeutics, the National Library of Medicine pointed out that other bifunctional therapies based on a similar mechanism have been discovered. These include deubiquitinase-targeting chimeras (DUBTACs), phosphorylation-inducing chimeras (PHICs), phosphatase-recruiting chimeras (PhoRCs), dephosphorylation-targeting chimeras (DEPTACs), phosphorylation-targeting chimeras (PhosTACs), acetylation tagging systems (AceTAGs), and transcriptional/epigenetic chemical inducers of proximity (TCIPs), all of which are in very early stages of preclinical research.
DUBTACs, like RIPTACs, are heterobifunctional molecules consisting of a protein-targeting ligand, but they are instead linked to a DUB recruiter via a linker. DUBs are deubiquitinating enzymes, which are proteases that remove ubiquitin tags from proteins, and so, DUBTACs aim to stabilize the levels of actively ubiquitinated proteins that are degraded by the proteasome. When treated in cells, a DUBTAC will induce the proximity of a DUB with a target protein to remove polyubiquitin chains to prevent the protein from undergoing proteasome-mediated degradation in order to stabilize protein levels, according to another report published in the National Library of Medicine. U.S.-based Vicinitas Therapeutics has licensed a platform from UC Berkeley and pharma giant Novartis to potentially lead DUBTAC therapeutics.
Aside from DUBTACs, PHICs are formed by linking small-molecule binders of the kinase and the target protein, whereas PhosTACs and DEPTACs, both of which are inspired by PROTACs, modulate protein phosphorylation by recruiting phosphatases to target proteins to aid in dephosphorylation – the process of removing a phosphate group from a protein. Meanwhile, AceTAGs induce the acetylation – adding an acetyl group – of target proteins.
With the first-ever RIPTAC now in the clinic, Halda also has a couple of other preclinical RIPTACs in development. Not much has been disclosed about the ones in the discovery stage, but its investigational New Drug (IND)-enabling candidate is currently being evaluated to treat hormone receptor positive (HR+) metastatic breast cancer.
As with HLD-0915, only time will tell whether or not it will survive the clinic. But with growing research on heterobifunctional molecules in cancer, the class of drugs could expand treatment options for a treatment-resistant and ever-evolving disease like cancer.
ADVERTISEMENT:
Halo, para pengemar slots pernahkah mendengar semboyan “slot gaco”? jika belum, siap-siap jatuh hati sama program ini. slot gaco merupakan mesin slot yang selalu memberi win. Yup, mesin-mesin ini bisa dibilang sebagai jagoannya tuk membawa come back hasil. but, gimana sih
tekniknya nemuin slot gaco yang tepat? Santuy Bro, kita bahas santai aja di tempat ini
Gaming terbaik waktu ini hanya satu berada Indonesia hanya di yang memberikan ROI terbesar
SEGERA hanya di :
Informasi mengenai KING SLOT, Segera Daftar Bersama king selot terbaik dan terpercaya no satu di Indonesia. Boleh mendaftar melalui sini king slot serta memberikan hasil kembali yang paling tinggi saat sekarang ini hanyalah KING SLOT atau Raja slot paling gacor, gilak dan gaco saat sekarang di Indonesia melalui program return tinggi di kingselot serta pg king slot
slot demo gacor
slot demo gacor permainan paling top dan garansi imbal balik hasil besar bersama kdwapp.com
akun demo slot gacor
akun demo slot gacor permainan paling top dan garansi imbal balik hasil besar bersama kdwapp.com
akun slot demo gacor
akun slot demo gacor permainan paling top dan garansi imbal balik hasil besar bersama kdwapp.com
akun demo slot pragmatic
akun demo slot pragmatic permainan paling top dan garansi imbal balik hasil besar bersama kdwapp.com
akun slot demo pragmatic
akun slot demo pragmatic permainan paling top dan garansi imbal balik hasil besar bersama kdwapp.com
akun slot demo
akun slot demo permainan paling top dan garansi imbal balik hasil besar bersama kdwapp.com
akun demo slot
akun demo slot permainan paling top dan garansi imbal balik hasil besar bersama kdwapp.com
slot demo gacor
slot demo gacor permainan paling top dan garansi imbal balik hasil besar bersama jebswagstore.com
akun demo slot gacor
akun demo slot gacor permainan paling top dan garansi imbal balik hasil besar bersama jebswagstore.com
akun slot demo gacor
akun slot demo gacor permainan paling top dan garansi imbal balik hasil besar bersama jebswagstore.com
akun demo slot pragmatic
akun demo slot pragmatic permainan paling top dan garansi imbal balik hasil besar bersama jebswagstore.com
akun slot demo pragmatic
akun slot demo pragmatic permainan paling top dan garansi imbal balik hasil besar bersama jebswagstore.com
akun slot demo
akun slot demo permainan paling top dan garansi imbal balik hasil besar bersama jebswagstore.com
akun demo slot
akun demo slot permainan paling top dan garansi imbal balik hasil besar bersama jebswagstore.com
slot demo gacor
slot demo gacor permainan paling top dan garansi imbal balik hasil besar bersama demoslotgacor.pro
akun demo slot gacor
akun demo slot gacor permainan paling top dan garansi imbal balik hasil besar bersama demoslotgacor.pro
akun slot demo gacor
akun slot demo gacor permainan paling top dan garansi imbal balik hasil besar bersama demoslotgacor.pro
akun demo slot pragmatic
akun demo slot pragmatic permainan paling top dan garansi imbal balik hasil besar bersama demoslotgacor.pro
akun slot demo pragmatic
akun slot demo pragmatic permainan paling top dan garansi imbal balik hasil besar bersama demoslotgacor.pro
akun slot demo
akun slot demo permainan paling top dan garansi imbal balik hasil besar bersama demoslotgacor.pro
akun demo slot
akun demo slot permainan paling top dan garansi imbal balik hasil besar bersama demoslotgacor.pro
slot demo gacor
slot demo gacor permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
akun demo slot gacor
akun demo slot gacor permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
akun slot demo gacor
akun slot demo gacor permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
akun demo slot pragmatic
akun demo slot pragmatic permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
akun slot demo pragmatic
akun slot demo pragmatic permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
akun slot demo
akun slot demo permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
akun demo slot
akun demo slot permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
situs slot terbaru
situs slot terbaru permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
slot terbaru
slot terbaru permainan paling top dan garansi imbal balik hasil besar bersama situsslotterbaru.net
suara88 permainan paling top dan garansi imbal balik hasil besar bersama suara88.biz
sumo7777 permainan paling top dan garansi imbal balik hasil besar bersama sumo7777.com
supermoney888 permainan paling top dan garansi imbal balik hasil besar bersama supermoney888.biz
teratai88 permainan paling top dan garansi imbal balik hasil besar bersama teratai88.biz
thor88 permainan paling top dan garansi imbal balik hasil besar bersama thor88.biz
togelhk88 permainan paling top dan garansi imbal balik hasil besar bersama togelhk88.net
topjitu88 permainan paling top dan garansi imbal balik hasil besar bersama topjitu88.net
totosloto88 permainan paling top dan garansi imbal balik hasil besar bersama totosloto88.com
trisula888 permainan paling top dan garansi imbal balik hasil besar bersama trisula888.biz
udangbet88 permainan paling top dan garansi imbal balik hasil besar bersama udangbet88.net
via88 permainan paling top dan garansi imbal balik hasil besar bersama via88.biz
virusjp88 permainan paling top dan garansi imbal balik hasil besar bersama virusjp88.net
warga888 permainan paling top dan garansi imbal balik hasil besar bersama warga888.biz
waw88 permainan paling top dan garansi imbal balik hasil besar bersama waw88.biz
winjitu88 permainan paling top dan garansi imbal balik hasil besar bersama winjitu88.net
wisdom88 permainan paling top dan garansi imbal balik hasil besar bersama wisdom88.biz
wnitogel88 permainan paling top dan garansi imbal balik hasil besar bersama wnitogel88.com
yoyo888 permainan paling top dan garansi imbal balik hasil besar bersama yoyo888.biz
validtoto88 permainan paling top dan garansi imbal balik hasil besar bersama validtoto88.com
sule999 permainan paling top dan garansi imbal balik hasil besar bersama sule999.com
sule88 permainan paling top dan garansi imbal balik hasil besar bersama sule88.org
ss888bet permainan paling top dan garansi imbal balik hasil besar bersama ss888bet.com
sia77 permainan paling top dan garansi imbal balik hasil besar bersama sia77.info
seluang88 permainan paling top dan garansi imbal balik hasil besar bersama seluang88.com
satu88 permainan paling top dan garansi imbal balik hasil besar bersama satu88.biz
satu777 permainan paling top dan garansi imbal balik hasil besar bersama satu777.asia
rp88 permainan paling top dan garansi imbal balik hasil besar bersama rp88.biz
rp88 permainan paling top dan garansi imbal balik hasil besar bersama rp88.asia
rp88 permainan paling top dan garansi imbal balik hasil besar bersama rp77.live
qiuqiu88 permainan paling top dan garansi imbal balik hasil besar bersama qiuqiu88.biz
pt88 permainan paling top dan garansi imbal balik hasil besar bersama pt88.org
pt77 permainan paling top dan garansi imbal balik hasil besar bersama pt77.info
produk88 permainan paling top dan garansi imbal balik hasil besar bersama produk88.asia
mt88 permainan paling top dan garansi imbal balik hasil besar bersama mt88.org
mt77 permainan paling top dan garansi imbal balik hasil besar bersama mt77.biz
menang66 permainan paling top dan garansi imbal balik hasil besar bersama menang66.biz
latobet888 permainan paling top dan garansi imbal balik hasil besar bersama latobet888.org
kedai96 permainan paling top dan garansi imbal balik hasil besar bersama kedai96.org
kedai188 permainan paling top dan garansi imbal balik hasil besar bersama kedai188.biz
ids88 permainan paling top dan garansi imbal balik hasil besar bersama ids88.biz
hp88 permainan paling top dan garansi imbal balik hasil besar bersama hp88.org
hp77 permainan paling top dan garansi imbal balik hasil besar bersama hp77.org
gm88 permainan paling top dan garansi imbal balik hasil besar bersama gm88.asia
gm77 permainan paling top dan garansi imbal balik hasil besar bersama gm77.net
final888 permainan paling top dan garansi imbal balik hasil besar bersama final888.org
duit88 permainan paling top dan garansi imbal balik hasil besar bersama duit88.asia
duit168 permainan paling top dan garansi imbal balik hasil besar bersama duit168.biz
divisi88 permainan paling top dan garansi imbal balik hasil besar bersama divisi88.org
dewi500 permainan paling top dan garansi imbal balik hasil besar bersama dewi500.biz
devil88 permainan paling top dan garansi imbal balik hasil besar bersama devil88.info
cuputoto88 permainan paling top dan garansi imbal balik hasil besar bersama cuputoto88.com
cukongbet88 permainan paling top dan garansi imbal balik hasil besar bersama cukongbet88.asia
bom888 permainan paling top dan garansi imbal balik hasil besar bersama bom888.biz
bintaro888 permainan paling top dan garansi imbal balik hasil besar bersama bintaro888.info
askasino88 permainan paling top dan garansi imbal balik hasil besar bersama askasino88.org
999aset permainan paling top dan garansi imbal balik hasil besar bersama 999aset.com
afb77 permainan paling top dan garansi imbal balik hasil besar bersama afb77.biz
aset99 permainan paling top dan garansi imbal balik hasil besar bersama aset99.biz
bendera77 permainan paling top dan garansi imbal balik hasil besar bersama bendera77.biz
bendera888 permainan paling top dan garansi imbal balik hasil besar bersama bendera888.com
coco88 permainan paling top dan garansi imbal balik hasil besar bersama coco88.org
cuma77 permainan paling top dan garansi imbal balik hasil besar bersama cuma77.biz
cuma88 permainan paling top dan garansi imbal balik hasil besar bersama cuma88.org
dwv88 permainan paling top dan garansi imbal balik hasil besar bersama dwv88.org
fafajp88 permainan paling top dan garansi imbal balik hasil besar bersama fafajp88.com
gemar88 permainan paling top dan garansi imbal balik hasil besar bersama gemar88.biz
gocap88 permainan paling top dan garansi imbal balik hasil besar bersama gocap88.info
gocaptoto permainan paling top dan garansi imbal balik hasil besar bersama gocaptoto.asia
hakabet88 permainan paling top dan garansi imbal balik hasil besar bersama hakabet88.com
hwtoto88 permainan paling top dan garansi imbal balik hasil besar bersama hwtoto88.org
ina77 permainan paling top dan garansi imbal balik hasil besar bersama ina77.biz
ina88 permainan paling top dan garansi imbal balik hasil besar bersama ina88.info
jingga8888 permainan paling top dan garansi imbal balik hasil besar bersama jingga8888.com
juragan777 permainan paling top dan garansi imbal balik hasil besar bersama juragan777.asia
kastil77 permainan paling top dan garansi imbal balik hasil besar bersama kastil77.info
kebo888 permainan paling top dan garansi imbal balik hasil besar bersama kebo888.biz
kkwin77 permainan paling top dan garansi imbal balik hasil besar bersama kkwin77.com
kokoslot88 permainan paling top dan garansi imbal balik hasil besar bersama kokoslot88.asia
luckydf88 permainan paling top dan garansi imbal balik hasil besar bersama luckydf88.org
microstar888 permainan paling top dan garansi imbal balik hasil besar bersama microstar888.biz
monperatoto88 permainan paling top dan garansi imbal balik hasil besar bersama monperatoto88.com
mpo1122 permainan paling top dan garansi imbal balik hasil besar bersama mpo1122.biz
mpo122 permainan paling top dan garansi imbal balik hasil besar bersama mpo122.biz
mpopelangi88 permainan paling top dan garansi imbal balik hasil besar bersama mpopelangi88.com
pamanslot88 permainan paling top dan garansi imbal balik hasil besar bersama pamanslot88.biz
panel88 permainan paling top dan garansi imbal balik hasil besar bersama panel88.org
paragon77 permainan paling top dan garansi imbal balik hasil besar bersama paragon77.biz
paragon888 permainan paling top dan garansi imbal balik hasil besar bersama paragon888.info
pion77 permainan paling top dan garansi imbal balik hasil besar bersama pion77.biz
prada88 permainan paling top dan garansi imbal balik hasil besar bersama prada88.asia
prada888 permainan paling top dan garansi imbal balik hasil besar bersama prada888.com
qqslot88slot permainan paling top dan garansi imbal balik hasil besar bersama qqslot88slot.com
rejekibet88 permainan paling top dan garansi imbal balik hasil besar bersama rejekibet88.com
rezekibet88 permainan paling top dan garansi imbal balik hasil besar bersama rezekibet88.org
sensa77 permainan paling top dan garansi imbal balik hasil besar bersama sensa77.biz
sensa888 permainan paling top dan garansi imbal balik hasil besar bersama sensa888.biz
singajp88 permainan paling top dan garansi imbal balik hasil besar bersama singajp88.com
sr77 permainan paling top dan garansi imbal balik hasil besar bersama sr77.org
sr88 permainan paling top dan garansi imbal balik hasil besar bersama sr88.org
surya77 permainan paling top dan garansi imbal balik hasil besar bersama surya77.biz
surya88 permainan paling top dan garansi imbal balik hasil besar bersama surya88.asia
tajir77 permainan paling top dan garansi imbal balik hasil besar bersama tajir77.info
tajir88 permainan paling top dan garansi imbal balik hasil besar bersama tajir88.biz
toto122 permainan paling top dan garansi imbal balik hasil besar bersama toto122.com
toto123 permainan paling top dan garansi imbal balik hasil besar bersama toto123.biz
uangvip88 permainan paling top dan garansi imbal balik hasil besar bersama uangvip88.com
wajik77 permainan paling top dan garansi imbal balik hasil besar bersama wajik77.asia
777neko permainan paling top dan garansi imbal balik hasil besar bersama 777neko.org
88judi permainan paling top dan garansi imbal balik hasil besar bersama 88judi.net
99judi permainan paling top dan garansi imbal balik hasil besar bersama 99judi.org
abcslot88 permainan paling top dan garansi imbal balik hasil besar bersama abcslot88.asia