A similar phenotype is observed in JAK3-deficient mice [11] and in a genetic
disorder called X-linked severe combined immunodeficiency (X-SCID), in which
the IL2RG gene is mutated [12]. However, although the impaired function of the
JAK3-γ c complex severely comprises immune response, these effects are mainly
limited to the immune system suggesting JAK3 as a promising target for the
treatment of inflammatory and autoimmune disorders with few side effects [13].
Although significant effort has recently been made to design selective
covalent JAK3 inhibitors, none of these compounds has been approved so far
(for an overview of approved covalent kinase inhibitors 1–5, see Fig. 2a). However,
several non-covalent JAK inhibitors with varying degrees of selectivity within the
JAK family and the kinome have gained approval or are in late-stage clinical trials
(Fig. 2b, c). The first JAK inhibitor that had been under clinical investigation
was CP-690,550 (tofacitinib, 6) [14], a compound developed by the US National
Institutes of Health (NIH) and Pfizer [15]. Tofacitinib was initially described as
a selective JAK3 inhibitor but later shown to target JAK1–3 and, to a lesser
degree, also TYK2 [16]. The compound was approved by the FDA in 2012 for the
treatment of rheumatoid arthritis (RA) and in May 2018 for the treatment of
ulcerative colitis [17]. The EMA, however, only granted approval in 2017 [18]
after re-evaluation of the application due to initial concerns regarding the
compound’s benefit-risk profile. In contrast, baricitinib (7), a JAK1/2 inhibitor
with good selectivity against JAK3, was approved in Europe in early 2017 as
a second-line therapy for the treatment of RA [19], while the FDA only granted
approval in May 2018 [20]. Interestingly, ruxolitinib (8), a structural analog of
baricitinib with a similar selectivity profile inside the JAK family, was already
approved by the FDA in late 2011 (EMA: 2012) for the treatment of myelofibrosis
[21] and later for polycythemia vera. Moreover, oclacitinib (9), a JAK inhibitor
closely resembling tofacitinib in terms of structure and selectivity, has gained
marketing authorization for veterinary purposes [22]. JAK inhibitors currently
under late-stage clinical development (phase III according to https://clinicaltrials.
gov) include the macrocyclic dual JAK2/FLT3 inhibitor pacritinib (10); the JAK1
inhibitors filgotinib (11), upadacitinib (12), PF-04965842 (13), and itacitinib (14);
the dual JAK1/2 inhibitor momelotinib (15); and the JAK3/pan-JAK inhibitor
decernotinib (16). However, it should be noted that these compounds generally
possess only a moderate degree of selectivity for individual JAK family members.
This can be attributed, at least in part, to the difficulties in designing truly isoformselective JAK inhibitors as a result of the striking similarity of the ATP pockets
within this family of protein kinases.
Non-covalent inhibitors with a certain degree of selectivity for JAK3 have also
been described (e.g., NIBR3049 (17), WYE-151650 (18), decernotinib (16), and
others (19–21); see Fig. 3 for selected examples) [23–28]. Among these compounds,
NIBR3049 (17), a low nanomolar JAK3 inhibitor, has the most pronounced JAK3
selectivity (127-fold, 318-fold, and 1,000-fold against JAK1, JAK2, and TYK2,
respectively) as determined in a biochemical Caliper assay format [29]. As
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disorder called X-linked severe combined immunodeficiency (X-SCID), in which
the IL2RG gene is mutated [12]. However, although the impaired function of the
JAK3-γ c complex severely comprises immune response, these effects are mainly
limited to the immune system suggesting JAK3 as a promising target for the
treatment of inflammatory and autoimmune disorders with few side effects [13].
Although significant effort has recently been made to design selective
covalent JAK3 inhibitors, none of these compounds has been approved so far
(for an overview of approved covalent kinase inhibitors 1–5, see Fig. 2a). However,
several non-covalent JAK inhibitors with varying degrees of selectivity within the
JAK family and the kinome have gained approval or are in late-stage clinical trials
(Fig. 2b, c). The first JAK inhibitor that had been under clinical investigation
was CP-690,550 (tofacitinib, 6) [14], a compound developed by the US National
Institutes of Health (NIH) and Pfizer [15]. Tofacitinib was initially described as
a selective JAK3 inhibitor but later shown to target JAK1–3 and, to a lesser
degree, also TYK2 [16]. The compound was approved by the FDA in 2012 for the
treatment of rheumatoid arthritis (RA) and in May 2018 for the treatment of
ulcerative colitis [17]. The EMA, however, only granted approval in 2017 [18]
after re-evaluation of the application due to initial concerns regarding the
compound’s benefit-risk profile. In contrast, baricitinib (7), a JAK1/2 inhibitor
with good selectivity against JAK3, was approved in Europe in early 2017 as
a second-line therapy for the treatment of RA [19], while the FDA only granted
approval in May 2018 [20]. Interestingly, ruxolitinib (8), a structural analog of
baricitinib with a similar selectivity profile inside the JAK family, was already
approved by the FDA in late 2011 (EMA: 2012) for the treatment of myelofibrosis
[21] and later for polycythemia vera. Moreover, oclacitinib (9), a JAK inhibitor
closely resembling tofacitinib in terms of structure and selectivity, has gained
marketing authorization for veterinary purposes [22]. JAK inhibitors currently
under late-stage clinical development (phase III according to https://clinicaltrials.
gov) include the macrocyclic dual JAK2/FLT3 inhibitor pacritinib (10); the JAK1
inhibitors filgotinib (11), upadacitinib (12), PF-04965842 (13), and itacitinib (14);
the dual JAK1/2 inhibitor momelotinib (15); and the JAK3/pan-JAK inhibitor
decernotinib (16). However, it should be noted that these compounds generally
possess only a moderate degree of selectivity for individual JAK family members.
This can be attributed, at least in part, to the difficulties in designing truly isoformselective JAK inhibitors as a result of the striking similarity of the ATP pockets
within this family of protein kinases.
Non-covalent inhibitors with a certain degree of selectivity for JAK3 have also
been described (e.g., NIBR3049 (17), WYE-151650 (18), decernotinib (16), and
others (19–21); see Fig. 3 for selected examples) [23–28]. Among these compounds,
NIBR3049 (17), a low nanomolar JAK3 inhibitor, has the most pronounced JAK3
selectivity (127-fold, 318-fold, and 1,000-fold against JAK1, JAK2, and TYK2,
respectively) as determined in a biochemical Caliper assay format [29]. As
228
M. Gehringer and M. Forster