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10 Therapies With Structures First Announced at AACR

 Last Update: 2022-06-16
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A few days ago, the 2022 annual meeting of the American Association for Cancer Research (AACR) came to an end

In their "New Drugs on the Horizon" series of reports, several biotech and pharmaceutical companies have published the molecular structures of their investigational therapies for the first time

Drug candidate: BAY 2666605, the first anticancer PDE3A-SLFN12 molecular glue

R&D institutions: Bayer, Broad Institute

▲ Molecular structural formula of BAY 2666605 (Image source: Reference [1])

BAY 2666605 is a molecular glue that promotes the formation of a complex between PDE3A and SLFN12, jointly developed by scientists at Bayer and the Broad Institute

Binding of PDE3A and SLFN12 stimulates the RNase activity of SLFN12, leading to cleavage of its specific substrate tRNA-Leu-TAA, and tRNA-Leu-TAA cleavage leads to ribosome stalling, inhibiting protein synthesis and leading to cancer cell death

Drug Candidate: CFT8634, Targeting BRD9 Protein Degrader

R&D Organization: C4 Therapeutics

▲ Molecular structural formula of CFT8634 (Image source: Reference [1])

▲ Molecular formula of CFT8634 (Image source: Reference [1]) CFT8634

The BRD9 protein targeted by CFT8634 is an important component of the SWI/SNF complex that controls chromatin remodeling and is frequently mutated in a variety of cancers

CFT8634 is a bispecific molecule that links BRD9 and the E3 ubiquitin ligase CRBN together, adding ubiquitin modification to the BRD9 protein, resulting in the specific degradation of BRD9

It has been granted orphan drug designation by the U.

CFT7455 promotes the degradation of IKZF1/3 by binding to the E3 ubiquitin ligase CRBN

▲ Molecular structural formula of CFT7455 (Image source: Reference [1])

Drug Candidate: FHD-286, an allosteric inhibitor of the BAF complex

R&D Organization: Foghorn Therapeutics

▲ Molecular structural formula of FHD-286 (Image source: Reference [1])

FHD-286 is a potential "first-in-class", oral inhibitor of the BAF complex

HD-286 inhibits the function of BAF by selectively inhibiting the ATPase components SMARCA4 and SMARCA2 in the BAF complex

▲ Introduction to FHD-286 (Image source: Foghorn Therapeutics)

Preclinical studies have shown that uveal melanoma and hematological cancer cell lines are particularly sensitive to BAF complex inhibitors

Uveal melanoma and hematological cancer cell lines are particularly sensitive to BAF complex inhibitors

Related reading: PROTAC combined with CRISPR screening, promising in this anti-cancer field

Drug Candidate: EZM0414, Histone Methyltransferase SETD2 Inhibitor

R&D organization: Epizyme

▲ Molecular formula of EZM0414 (Image source: Reference [1])

EZM0414, like FHD-286 and CFT8634 mentioned above, is designed to treat cancer by targeting epigenetic mechanisms

Tazverik is the first FDA-approved EZH2 inhibitor

EZM0414 is a potential "first-in-class" SETD2 inhibitor

Drug Candidate: ABBV-CLS-484, Phosphatase PTPN2/N1 Inhibitor

R&D institutions: AbbVie, Calico, Broad Institute

▲ ABBV-CLS-484 molecular structure (picture source: Reference [1])

PTPN2/N1 are protein tyrosine phosphatases, and their function is to remove the added phosphate group on tyrosine

Drug Candidate: KSQ-4279, Potential "first-in-class" Allosteric USP1 Inhibitor

R&D organization: KSQ Therapeutics

▲ Molecular structural formula of KSQ-4279 (Image source: Reference [1])

KSQ-4279 is a potent and selective allosteric inhibitor of USP1, a member of the ubiquitin-specific processing protein family that plays an important role in the DNA damage response
.
Using its CRISPR-screen-based CRISPRomics technology platform, KSQ Therapeutics discovered that USP1 is an innovative synthetic lethal target for specific genomically unstable cancers
.

Using its CRISPR-screen-based CRISPRomics technology platform, KSQ Therapeutics discovered that USP1 is an innovative synthetic lethal target for specific genomically unstable cancers
.

The allosteric inhibitory feature of KSQ-4279 makes it highly selective for USP1, significantly superior to other USP protein families
.
Preclinical studies have shown that it is effective as a single agent or in combination with a PARP inhibitor in multiple cancer models harboring BRCA mutations or homologous recombination deficiency
.

Furthermore, a functional genomic resistance screen found that the genetic factors driving resistance to USP1 inhibitors did not overlap with those driving resistance to PARP inhibitors
.
This means that the combination may delay or prevent the development of resistance
.
At present, KSQ Therapeutics has initiated a phase 1 clinical trial to evaluate its effect in patients with advanced solid tumors
.

Genetic factors driving resistance to USP1 inhibitors do not overlap with those driving resistance to PARP inhibitors
.
This means the combination may delay or prevent the development of resistance

Drug Candidate: MRTX0902, a SOS1 inhibitor targeting KRAS-driven cancers

R&D Organization: Mirati Therapeutics

▲Molecular structural formula of MRTX0902 (Image source: Reference [1])

Efforts to target KRAS G12C have seen major breakthroughs in the past few years, with both Amgen's sotorasib and Mirati's adagrasib (MRTX849) showing activity in clinical trials
.
The SOS protein is a guanine nucleotide exchange factor (GEF) that plays an important role in the activation of RAS family proteins
.

The SOS protein is a guanine nucleotide exchange factor (GEF) that plays an important role in the activation of RAS family proteins
.

MRTX0902 is a potent and selective oral inhibitor of SOS1
.
Using structure-based design, Mirati scientists discovered a series of compounds that disrupt the interaction between SOS1 and KRAS, preventing SOS1-mediated GTP substitution of GDP bound to KRAS
.
The KRAS bound to GDP is in an inactive state, and adagrasib can bind to the inactive KRAS G12C, inhibiting its activity
.
Therefore, the combination of MRTX0902 and adagrasib is expected to further enhance the effect of adagrasib
.

▲The mechanism of action of MRTX0902 (Image source: Mirati's official website)

Therapeutic Candidate: GDC-6036, Oral KRAS G12C Covalent Inhibitor

R&D organization: Genentech

▲GDC-6036 molecular structure (picture source: Reference [1])

GDC-6036 developed by Genentech, a subsidiary of Roche, is a KRAS G12C covalent inhibitor.
It has the same mechanism of action as Amgen's sotorasib and Mirati's adagrasib .
KRAS is locked in an inactive state
.
It is currently in Phase 1 clinical trials as a single agent, as well as in combination with other anti-cancer therapies, for the treatment of non-small cell carcinoma, colorectal cancer and other cancer types that carry the KRAS G12C mutation
.

KRAS is locked in the inactive state by binding to the inactive state of KRAS G12C
.

Drug Candidate: NPX800, Heat Shock Factor 1 (HSF1) Inhibitor

R&D facilities: London Institute of Cancer Research, Nuvectis Pharma

▲ Molecular formula of NPX800 (Image source: Reference [1])

HSF1 is a stress-inducible transcription factor that plays a key role in triggering the heat shock response in eukaryotic cells
.
In cancer cells, HSF1 is "hijacked" to trigger gene expression similar to the classical heat shock response
.
The HSF1 signaling pathway plays an important role in tumorigenesis and is an anticancer drug target validated by many studies
.

In cancer cells, HSF1 is "hijacked" to trigger gene expression similar to the classical heat shock response
.

Researchers at the Institute of Cancer Research, London, initially identified compounds that inhibit HSF1 activity through phenotypic screening, and worked with Nuvectis Pharma to optimize them into clinical-stage drug candidates
.
NXP800 is a potential "first-in-class", oral HSF1 signaling pathway inhibitor
.
It is currently being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors
.

References:

[1] New Drug Candidates at AACR New Orleans 2022.
Retrieved April 11, 2022, from https://drughunter.
com/new-drug-candidates-at-aacr-new-orleans-2022/

[2] KSQ Therapeutics To Present Data At The American Association For Cancer Research (AACR) 2022 Annual Meeting.
Retrieved April 11, 2022, from https://ksqtx.
com/news-events/ksq-therapeutics-to-present-data -at-the-american-association-for-cancer-research-aacr-2022-annual-meeting/

[3] NXP800: A first-in-class, orally active, smallmolecule HSF1* pathway inhibitor.
Retrieved April 12, 2022, from https://nuvectis.
com/wp-content/uploads/2022/04/NXP800-New- Drugs-on-the-Horizon_-AACR-2022.
pdf

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