| Candidate ID: | R1018 |
| Source ID: | DB06448 |
| Source Type: | approved; investigational |
| Compound Type: |
small molecule
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| Compound Name: |
Lonafarnib
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| Synonyms: |
--
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| Molecular Formula: |
C27H31Br2ClN4O2
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| SMILES: |
NC(=O)N1CCC(CC(=O)N2CCC(CC2)[C@H]2C3=C(CCC4=C2C(Br)=CC(Cl)=C4)C=C(Br)C=N3)CC1
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| Structure: |
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| DrugBank Description: |
Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in adverse symptoms associated with premature ageing: skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive; HGPS is uniformly fatal. Mechanistically, HGPS is underpinned by a single heterozygous C-to-T mutation at position 1824 of the _LMNA_ gene, which results in the accumulation of an aberrant farnesylated form of lamin A called progerin in the inner nuclear membrane. Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), which reduces the farnesylation of numerous cellular proteins, including progerin; as progerin farnesylation is important for localization to the nuclear membrane, lonafarnib inhibits progerin accumulation and improves symptoms in HGPS patients.
Merck originally developed Lonafarnib and subsequently licensed it to Eiger Biopharmaceuticals Inc., which currently markets it under the trademark ZOKINVY™. Lonafarnib was granted FDA approval on November 20, 2020, and is the first FDA-approved treatment for HGPS and other related progeroid laminopathies.
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| CAS Number: |
193275-84-2
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| Molecular Weight: |
638.822
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| DrugBank Indication: |
Lonafarnib is a farnesyltransferase inhibitor indicated in patients aged 12 months and older with a body surface area of at least 0.39 m<sup>2</sup> to reduce the risk of mortality associated with Hutchinson-Gilford progeria syndrome (HGPS). It is also indicated in this same population for the treatment of processing-deficient progeroid laminopathies that either involve a heterozygous _LMNA_ mutation resulting in the accumulation of a progerin-like protein or homozygous/compound heterozygous mutations in _ZMPSTE24_.
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| DrugBank Pharmacology: |
Lonafarnib is a direct farnesyl transferase inhibitor that reduces the farnesylation of numerous cellular proteins, including progerin, the aberrantly truncated form of lamin A that accumulates in progeroid laminopathies such as Hutchinson-Gilford progeria syndrome. Treatment with lonafarnib has been associated with electrolyte abnormalities, myelosuppression, and increased liver enzyme levels (AST/ALT), although causation remains unclear. Also, lonafarnib is known to cause nephrotoxicity in rats and rod-dependent low-light vision decline in monkeys at plasma levels similar to those achieved under recommended dosing guidelines in humans; patients taking lonafarnib should undergo regular monitoring for both renal and ophthalmological function. In addition, based on observations from animal studies with rats, monkeys, and rabbits with plasma drug concentrations approximately equal to those attained in humans, lonafarnib may cause both male and female fertility impairment and embryo-fetal toxicity.
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| DrugBank MoA: |
Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in premature ageing, associated cardiovascular, cerebrovascular, and musculoskeletal effects and early death around 14 years of age. The _LMNA_ gene encodes lamin A and lamin C, two proteins involved in nuclear integrity and function at the inner nuclear membrane. Under normal conditions, the 12-exon _LMNA_ gene produces full-length prelamin A, which undergoes farnesylation of the C-terminal _CaaX_ motif, followed by proteolytic cleavage of the terminal three amino acids (_aaX_) by the metalloproteinase ZMPSTE24, subsequent carboxymethylation, and finally removal of the last 15 amino acids to yield mature, unfarnesylated, lamin A protein. In HGPS, a single heterozygous C-to-T mutation at position 1824 results in a cryptic splice site that removes the last 150 nucleotides of exon 11 and a concomitant 50-amino acid deletion in the C-terminus of the prelamin A protein. This aberrant prelamin A protein, often called progerin, is permanently farnesylated but unable to complete maturation due to the removal of the second endoproteolytic cleavage site.
Although the exact mechanism is unclear, progerin accumulation results in a host of adverse symptoms associated with ageing such as skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive. An additional notable effect of HGPS is increased vascular and peripheral calcification. Children affected by HGPS typically die due to myocardial infarction or stroke. Mechanistic understanding of HGPS remains unclear, although a recent study correlated progerin accumulation, telomere dysfunction, DNA damage-mediated inflammatory cytokine release, and HGPS symptoms, suggesting that the nuclear effects of progerin accumulation may result in pleiotropic downstream effects.
Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), with a reported IC<sub>50</sub> value of 1.9 nM; lonafarnib is specific for FTase, as it does not appreciably inhibit the related GGPT-1 enzyme at concentrations up to 50 μM. Inhibition of progerin farnesylation reduces progerin accumulation in the inner nuclear membrane, which subsequently slows the progression of HGPS and other progeroid laminopathies.
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| Targets: |
Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha inhibitor; Protein farnesyltransferase subunit beta inhibitor
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| Inclusion Criteria: |
Therapeutic strategy associated
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