Famlasertib

CAS 2375591-69-6

MFC26H27ClN4O MW 447.0 g/mol

4-[[4-[3-(3-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]-1-piperazineethanol

2-[4-({4-[3-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]phenyl}methyl)piperazin-1-yl]ethan-1-ol
serine/threonine kinase inhibitor, amyotrophic lateral sclerosis, Prosetin, WJP32276AY

Prosetin is an orally administered blocker of MAP4K under investigation for the treatment of amyotrophic lateral sclerosis.

Famlasertib (also known as Prosetin or Prostetin/12k) is a highly potent, small-molecule inhibitor targeting the mitogen-activated protein kinase kinase kinase kinase (MAP4K) family. It is an experimental drug primarily under investigation for its neuroprotective capabilities in treating neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and as an anti-invasive agent in certain cancers

• Target Pathways: MAP4K4 (HGK), MLK1, and MLK3
• Key Properties: Orally active, blood-brain barrier penetrant (CNS-penetrant)

Mechanism of Action

Famlasertib functions by blocking the activation of the MAP4K protein family, specifically demonstrating powerful inhibitory values (\(\text{IC}_{50}\)) against subfamilies like HGK (MAP4K4), MLK3, and MLK1. By inhibiting these kinases, the compound: [1]

• Reduces Endoplasmic Reticulum (ER) Stress: It helps mitigate the unfolded protein response that triggers programmed cell death in neurons affected by misfolded protein accumulation.
• Suppresses Inflammation: It blocks inflammatory pathways associated with neurodegeneration and cell damage.
• Restrains Cell Motility: In oncology contexts, it disrupts kinase signaling linked to actin cytoskeleton remodeling, preventing malignant cells from migrating.

Primary Areas of Research

1. Amyotrophic Lateral Sclerosis (ALS)

In motor neuron models of ALS, cellular stress frequently triggers neurodegeneration. Because famlasertib easily passes through the blood-brain barrier, it is capable of directly shielding motor neurons from ER-stress-mediated cell death, extending cell viability in laboratory models.

2. Oncology (Medulloblastoma)

Recent findings published on bioRxiv indicate that famlasertib acts as a “migrastatic” agent in medulloblastoma (a type of pediatric brain tumor). It suppresses the highly invasive behavior and single-cell motility of tumor cells without exhibiting developmental toxicity.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020163594&_cid=P21-MPGALG-31359-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US317630245&_cid=P21-MPGALG-31359-1

Preparation of 2-(4-(4-(3-(3-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperazin-1-yl)ethan-1-ol (Compound 12k)

Following the general procedure described above, with 4-(3-(3-chlorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzaldehyde (10c, 418 mg, 0.86 mmol) and 1-(2-hydroxyethyl)piperazine (224 mg, 211 μL, 1.72 mmol, 2.0 eq) as the starting materials, 2-(4-(4-(3-(3-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperazin-1-yl)ethan-1-ol (12k) was isolated as an off-white solid (139.9 mg, 36% yield over two steps). 1H NMR (400 MHz, Methanol-d ₄) δ 8.57 (d, J=2.0 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.65 (t, J=1.9 Hz, 1H), 7.64-7.57 (m, 3H), 7.42 (t, J=7.9 Hz, 1H), 7.29 (ddd, J=8.0, 2.1, 1.0 Hz, 1H), 4.27 (s, 2H), 3.93-3.86 (m, 2H), 3.62 (s, 4H), 3.41 (s, 4H), 3.35-3.31 (m, 2H) ppm. HRMS (APCI ⁺, m/z): calcd. for C ₂₆H ₂₈N ₄₀Cl [M+H ⁺]: 447.1952, found: 447.1954.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US469942811&_cid=P21-MPGAUU-39605-1

ADVT

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References

• Design, synthesis of new 3H-imidazo[4,5-b]pyridine derivatives and evaluation of their inhibitory properties as mixed lineage kinase 3 inhibitorsPublication Name: Bioorganic & Medicinal Chemistry LettersPublication Date: 2024-03-15PMID: 38346577DOI: 10.1016/j.bmcl.2024.129652
• The emerging role of mixed lineage kinase 3 (MLK3) and its potential as a target for neurodegenerative diseases therapiesPublication Name: European Journal of Medicinal ChemistryPublication Date: 2023-09-05PMID: 37247505DOI: 10.1016/j.ejmech.2023.115511
• Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting AgentsPublication Name: Cell Chemical BiologyPublication Date: 2019-12-19PMCID: PMC7253076PMID: 31676236DOI: 10.1016/j.chembiol.2019.10.005

PAT

• Immunophilin binding agents and uses thereofPublication Number: US-2023063768-A1Priority Date: 2019-02-07
• Immunophilin binding agents and uses thereofPublication Number: WO-2020163594-A1Priority Date: 2019-02-07
• Immunophilin-dependent inhibitors and uses thereofPublication Number: US-2022193242-A1Priority Date: 2019-02-07
• Immunophilin-dependent inhibitors and uses thereofPublication Number: WO-2020163598-A1Priority Date: 2019-02-07
• Compounds, compositions and methods for inhibiting toxic endoplasmic reticulum stress – Patents.comPublication Number: JP-7487170-B2Priority Date: 2018-03-01Grant Date: 2024-05-20
• Compounds, compositions, and methods for suppressing toxic endoplasmic reticulum stress
• Publication Number: US-2021040091-A1
• Priority Date: 2018-03-01G

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