▎ WuXi AppTec content team editor
A few days ago, the American Association for Cancer Research (AACR) 2022 annual meeting came to an end. AACR is one of the world's largest cancer research conferences, bringing together high-quality oncology research and clinical advances from around the globe. In its "New Drugs on the Horizon" series of reports, several biotechnology and pharmaceutical companies have published for the first time the molecular structure of therapies in research. The Drug Hunter website (drughunter.com) summarizes these small molecule drugs. Today, WuXi AppTec's content team will introduce these innovative small molecule therapies in conjunction with reports and publicly available materials from the Drug Hunter website.
Drug candidate: BAY 2666605, the first anti-cancer PDE3A-SLFN12 molecular glue
R&D institution: Bayer, Broad Institute
▲Molecular structural formula of BAY 2666605 (Image source: Reference[1])
BAY 2666605 is a molecular glue jointly developed by scientists from Bayer and the Broad Institute to facilitate the formation of a complex of PDE3A and SLFN12. PDE3A and SLFN12 are two proteins that are overexpressed in a variety of cancers. The binding of PDE3A and SLFN12 stimulates the RNase activity of SLFN12, leading to cleavage of its specific substrate tRNA-Leu-TAA, while cleavage of tRNA-Leu-TAA causes ribosomes to pause, inhibits protein synthesis and leads to cancer cell death.
BAY 2666605 has entered Phase 1 clinical trials for the treatment of patients with advanced solid tumors expressing both PDE3A and SLFN12, including melanoma, ovarian cancer, and sarcoma.
Drug candidate: CFT8634, targeting BRD9 protein degrader
R&D organization: C4 Therapeutics
▲CFT8634 molecular structural formula (Image source: Reference[1])
The BRD9 protein targeted by CFT8634 is an important component of the SWIA/SNF complex that controls chromatin remodeling, which often mutates in a variety of cancers. CFT8634 is a bispecific molecule that can bind BRD9 and E3 ubiquitin link enzyme CRBN together, adding ubiquitin modifications to the BRD9 protein, resulting in specific degradation of BRD9.
In a preclinical model of synovial sarcoma, CFT8634 exhibited a sustained effect of reducing tumor volume. The therapies under investigation have been granted the FDA as orphan drugs for the treatment of synovial sarcoma, and their IND application was licensed at the end of February this year, and it is expected to begin Phase 1 clinical trials for patients with synovial sarcoma in the first half of the year.
C4 Therapeutics also presented the results of a preliminary clinical trial of crBN E3 ligase modulator (CELMoDs) CFT7455 as a monotherapy for patients with relapsed/refractory multiple myeloma at the AACR Conference. CFT7455 promotes the degradation of IKZF1/3 by binding to the E3 ubiquitin ligase CRBN.
▲CFT7455 molecular structural formula (Image source: Reference[1])
Drug candidate: FHD-286, BAF complex allosterical inhibitor
R&D organization: Foghorn Therapeutics
▲FHD-286 molecular structural formula (Image source: Reference[1])
FHD-286 is a potential "first-in-class", BAF complex oral inhibitor. BaF complexes (aka SWI/SNF complexes) play an important role in the epigenetic regulation of DNA. In many cancers, changes in epigenetic regulation lead to overexpression of oncogenes or inhibition of expression of tumor suppressor genes, triggering cancerous changes in cells. FHD-286 inhibits the function of BAF by selecting sex structures to inhibit 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 blood cancer cell lines are particularly sensitive to BAF complex inhibitors. Currently, FHD-286 is being tested in two Phase 1 clinical trials for the treatment of relapsed/refractory acute myeloid leukemia and metastatic uveal melanoma. The company is also using strategies that target protein degradation to degrade BAF complexes, and its research therapy for degrading BRD9, FHD-609, has also entered clinical trials.
Drug candidate: EZM0414, inhibitor of histone methyltransferase SETD2
R&D organization: Epizyme
▲EZM0414 molecular structure formula (Image source: Reference[1])
EZM0414, like the FHD-286 and CFT8634 mentioned above, is designed to treat cancer by targeting epigenetic mechanisms. Epizyme is committed to the development of innovative therapies targeted for epigenetic regulation. Its EZH2 inhibitor, Tazverik, is the first FDA-approved EZH2 inhibitor, a catalytic subunit of histone methyltransferase PRC2. Tazverik's approval also provides clinical validation of strategies for targeting epigenetic mechanisms to treat cancer.
EZM0414 is a potential "first-in-class" SETD2 inhibitor. SETD2 is a histone methyltransferase that has a similar effect to PCR2. EZM0414 has been granted fast-track qualification by the U.S. FDA for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Epizyme has launched Phase 1 clinical trials to test its effectiveness in patients with multiple myeloma and DLBCL.
Drug candidate: ABBV-CLS-484, inhibitor of phosphatase PTPN2/N1
R&D institutions: AbbVie, Calico, Broad Institute
ABBV-CLS-484 molecular structural formula (Image source: Reference[1])
PTPN2/N1 is a protein tyrosine phosphatase whose role is to remove phosphate groups added to tyrosine. Plays an important role in multiple steps of the cancer immune response. For example, PTPN2 can regulate the production of depleted CD8-positive T cells. Phosphatase is a target that is difficult to target, because its catalytic subunit part is highly conserved, and drugs that target catalytic subunits can easily inhibit the activity of other phosphatase at the same time, resulting in toxic side effects. ABBV-CLS-484 is an inhibitor that targets the PTPN2 active site and inhibits its activity at pM levels. AbbVie has conducted Phase 1 clinical trials to test its effects in combination with immune checkpoint inhibitors.
Drug candidate: KSQ-4279, a potential "first-in-class" allostereomer USP1 inhibitor
R&D organization: KSQ Therapeutics
KSQ-4279 molecular structure formula (Image source: Reference[1])
KSQ-4279 is a potently selective ALLOSOME inhibitor of USP1, a family of ubiquitin-specific processing proteins that play an important role in DNA damage responses. KSQ Therapeutics, using its CRISPR-based screening-based CRISPR-based CRISPS Technology platform, found that USP1 is an innovative synthetic lethal target for specific genomically unstable cancers.
The allosteric inhibition of KSQ-4279 makes it highly selective for USP1 and significantly better than other USP protein families. Preclinical studies have shown efficacy in multiple cancer models carrying BRCA mutations or homologous recombinant defects as a monotherapy agent or in combination with PARP inhibitors.
Moreover, functional genomic resistance screening found that the genetic factors driving resistance to USP1 inhibitors did not overlap with the genetic factors driving PARP inhibitor resistance. This means that this combination may delay or prevent the development of drug resistance. KSQ Therapeutics has initiated Phase 1 clinical trials to assess its effectiveness in patients with advanced solid tumors.
Drug candidate: MRTX0902, an SOS1 inhibitor for KRAS-driven cancer
R&D organization: Mirati Therapeutics
▲MRTX0902 molecular structural formula (Image source: Reference[1])
Efforts to target KRAS G12C have led to major breakthroughs over the past few years, with Both Amgen's sotoorasib and Mirati's Adagrasib (MRTX849) demonstrating activity in clinical trials. SoS protein is a guanine nucleotide exchange factor (GEF) that plays an important role in activating the RAS family of proteins.
MRTX0902 is a potent and selective oral inhibitor of SOS1. Using a structure-based design, Mirati's scientists found a range of compounds that could disrupt the interaction between SOS1 and KRAS, preventing SOS1 from mediating GTP to replace GDP bound to KRAS. Kras combined with GDP is inactivated, while adagrasib is able to bind to KRAS G12C in an inactive state, 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 official website)
Candidate therapy: GDC-6036, an oral KRAS G12C covalent inhibitor
R&D institution: Genentech
▲GDC-6036 molecular structure formula (Image source: Reference[1])
GDC-6036, developed by Roche's Genentech Corporation, is a KRAS G12C covalent inhibitor that has the same mechanism of action as Azurasib and Adagrasib developed by Mirati, locking KRAS in an inactive state by combining with the inactive KRAS G12C. It is currently being used as a monotherapy in Phase 1 clinical trials, in combination with other anti-cancer therapies, to treat types of cancer that carry KRASG12C mutations, such as non-small cell carcinoma and colorectal cancer.
Drug candidate: NPX800, heat shock factor 1 (HSF1) inhibitor
R&D agency: Cancer Institute London, Nuvectis Pharma
▲NPX800 molecular structural formula (Image source: Reference[1])
HSF1 is a stress-induced transcription factor that plays a key role in stimulating the heat shock response of eukaryotic cells. In cancer cells, HSF1 is "hijacked" to stimulate gene expression similar to the classical heat shock response. The HSF1 signaling pathway plays an important role in tumorigenesis and is a target of anticancer drugs validated by multiple studies.
Researchers at the Cancer Institute London initially identified compounds that inhibit HSF1 activity through phenotypic screening and worked with Nuvectis Pharma to optimize them as clinical-phase drug candidates. NXP800 is a potential "first-in-class" inhibitor of the HSF1 signaling pathway. It is currently being evaluated in a Phase 1 clinical trial for the treatment of patients with advanced solid tumors.
Resources:
[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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