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.pdf
N
https://t.me/med1917
O
21
Original hit (2010)
7.3 Pharmacological Mechanisms of Splicing Modulation 185
N
N
O
O
• Potency greatly enhanced by basic
amine (>pKa 7)
• Potency enhanced when orientation
of methyl groups and azine
reinforced by an anti-coplanar
relationship
• Potency best with methyl groups
and azine nitrogen
N
HN
Milestone lead (2010)
36
N
N
O
O
N
N
N
N
First in human trials (2014)
• Plasma exposure improved with N-
substitution
• Plasma exposure improved with
methylation
• Plasma exposure and brain/plasma
distribution best with pyrido pyrimidine core
• Plasma exposure and brain/plasma
ratio improved with alkylation
O
RG7800
N
N
N
N
N
HN
FDA approved (2020)
• H avoids formation of potentially
toxic peripherally-active metabolite
• Cyclopropyl reduces basicity,
suppressing hERG inhibition
and phospholipidosis in turn
• Imidazopyridazine abolishes
phototoxicity and improves potency
O
risdiplam
N
N
N
Figure 7.26 Development evolution of risdiplam. Major structure–activity,
structure–toxicity, and structure–pharmacokinetic relationships highlighted.
for noncanonical −2G/−1A 5′-splice sites – which enforces an inherent limitation
on the number of potential on-mechanism/o-target splicing events – and the
fact that SMN2 is the most responsive gene to risdiplam treatment. However,
toxicity is evident at high doses in animals – an observation around which two
competing interpretations have evolved. The rst claims toxicity is a consequence
of compound-induced splicing of specic key regulatory genes (e.g. FOXM1 and
MADD) [207], whereas the second ascribes toxicity to the absolute number of genes
186 7 Pre-mRNA Splicing Modulation
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dysregulated at a given concentration (i.e. the “splicing burden”) [208]. At this time,
however, no systematic study exists that resolves these perspectives or provides
conclusive guidance on the topic of splicing-related toxicity in the design of future
splicing modulators.
Ultimately, risdiplam teaches that (i) the genesis of new programs may still be
found in target-agnostic high-throughput screening and (ii) medicinal chemists may
continue to rely on their traditional phenotypic tools of the art; detailed mechanistic
insight is not required. Perhaps most importantly,risdiplam’s approval is validation
that therapeutic manipulation of splicing can be a safe and eective strategy in the
correction of human disease.
7.4 Future Outlook
It should be evident that not all mechanisms of pre-mRNA splicing modulation are
equal, and that some present greater challenges than others. However, the discovery
and development of small-molecule splicing modulators has unmistakably matured
since the crude seminal demonstrations of the 1990s – from weak and nonselective kinase inhibitors to potent and selective spliceosome modulators. Where then
is splicing modulation heading? What new technologies will enable small-molecule
discovery?
Until very recently, splicing drug discovery was focused on modulation of naturally regulated exons and introns, but considerable activity is now concentrated in
the development of small-molecule inducers of unnatural pseudoexons – intronic
sequences not normally found in mRNA despite ostensible possession of requisite
splicing features (Figure 7.3). Among the dierent types of pseudoexons, those
that introduce premature stop codons (PTCs) into mRNA are of greatest interest
because PTC-containing mRNAs are susceptible to degradation through a protective
cellular process called NMD (Figures 7.27a,b) [209, 210]. Therefore, small-molecule
promoters of PTC pseudoexon inclusion are expected to downregulate target
gene expression. An example leveraging this mechanism can be found in PTC
Therapeutic’s Huntington Disease program, for which their clinical candidate
PTC518 is undergoing Phase II trials. Huntington disease is a nucleotide repeat
disorder originating from a (CAG)ntriplet repeat expansion in exon 1 of the HTT
gene because this mutant HTT encodes a toxic protein that accounts for much
of the pathology, it is benecial to minimize its expression [211, 212]. In 2021,
researchers at PTC Therapeutics demonstrated that pseudoexons handicapped by
noncanonical 5′ss sequences but otherwise resembling true exons could be activated
by complementary variant U1 snRNAs, allowing the researchers to map potentially
druggable targets in the genome [179]. Among these, a PTC-containing pseudoexon
in HTT intron 49 was discovered whose inclusion (i) was induced by branaplamand risdiplam-type splicing modulators and (ii) lead to HTT mRNA degradation
and – most importantly – therapeutically meaningful in vivo protein reduction
(Figure 7.27c). Since then, many new companies platformed on inducible pseudoexon alternative splicing have emerged [213], and although outlook is optimistic,
PTC
https://t.me/med1917
7.4 Future Outlook 187
(a)
(b)
Exon 1
psi-3’ss
Psi 1
psi-5’ss
Exon 2
Nucleotides = 3n
PTC
Exon 1
Psi 1
Exon 2
mRNA degraded via nonsense-mediated decay (NMD)
Exon 1
psi-3’ss
Psi 1
psi-5’ss
Exon 2
Nucleotides = 3n+1
or Nucleotides = 3n+2
PTC
Exon 1
Psi 1
Exon 2
mRNA degraded via nonsense-mediated decay (NMD)
(CAG)
Exon 1
(c)
mRNA degraded via nonsense-mediated decay (NMD)
Figure 7.27 Two common modes of pseudoexon-induced nonsense-mediated decay.
(a) The pseudoexon can contain a premature stop codon (PTC); (b) pseudoexon sequences
composed of a number of nucleotides not divisible by three (nt = 3n+1, nt = 3n+2) may
introduce premature stop codons due to frameshift of downstream exons;
(c) compound-induced inclusion of pseudoexon 49a in the (CAG)nmutant HTT gene
introduces a premature stop codon into the final mRNA transcript, which is then degraded
through nonsense-mediated decay.
n
(CAG)
Exon 49 Exon 50
n
Psi 49a
Exon 1 Exon 49 Exon 50Psi 49a
PTC
PTC
188 7 Pre-mRNA Splicing Modulation
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it must be said that the state of the art is currently restricted to noncanonical 5′-ss
pseudoexons and derivatives of branaplam and risdiplam [214, 215].
Another area of exceptional interest is the design of RNA-targeted focused
libraries composed of compounds complementary to the unique physicochemical
properties of RNA [216–218]. Evidence supporting this strategy is illustrated by
Pzer’s discovery of CD33 splicing modulators [219]. CD33 is a protein for which
exon 2 skipping aords a benecial variant associated with protection in late-onset
Alzheimer’s disease. Seeking small-molecule eectors of CD33 pre-mRNA alternative splicing, the company screened >3 million compounds and uncovered a
cluster of hits originating from an older (albeit nonsplicing) RNA-targeting program
[220, 221]. These compounds were originally optimized to inhibit translation of
PCSK9 – a protein regulator of plasma cholesterol levels – by binding a ribosomal
RNA–protein interface [177, 222, 223]. Although the mechanism of CD33 exon 2
skipping remains unreported, it is nonetheless remarkable that among millions of
compounds, only those with established RNA-interacting ability were identied as
developable splicing modulators.
Finally, the application of RNA sequencing (RNA-seq) to small-molecule discovery nds alluring prospect. Originally developed in 2007 for the analysis of
dierential gene expression, RNA-seq provides a multidimensional, high-content
strategy for screening chemical libraries. A major disadvantage, however, is price.
Although much more aordable now than 15 years ago, the technique still demands
costs-per-compound well above traditional high-throughput screening, but recent
adaptations have improved accessibility. For example, RASL-seq is a focused
technique with excellent sensitivity but limited gene coverage [224, 225], BRB-seq
and Tru-seq reduce the number of sequencing analyses through use of barcoding
strategies that permit unambiguous deconvolution of multiplexed samples [226],
and Novartis’ DRUG-seq is a higher throughput modication of BRB-seq that
obviates the need for RNA purication [227, 228]. Although these unconventional
screening platforms have not yet been reported in the discovery of new splicing
modulators, they are auspicious portents of an exciting and innovative future.
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