Potential Future Avenues for JAK2 Inhibitor Development and Alternative Therapeutic Approaches

[Manouche]

« While current JAK2 inhibitors in clinical development all act via ATP competitive binding to the active conformation of the JAK2 kinase domain (type 1 inhibition), perspectives for the future development of enhanced JAK2 inhibitors include several alternative approaches.

Selective inhibition of JAK2 V617F represents an ultimate goal and would hopefully facilitate efforts to reduce MPN clone size. Type 2 JAK2 inhibition, which interferes with JAK2 in the inactive conformation, has shown promising effects on mutant allele burden in preclinical studies [85,86]. A different concept is the design of JAK2 pseudokinase inhibitors displacing ATP from the JAK2 JH2 domain. While minor effects on wild-type JAK2 have been detected, JH2 ATP binding appears to be critical for aberrant constitutive activity in JAK2 V617F [87].

Promising results are accumulating for combining JAK2 inhibition with the targeting of additional factors involved in MPN pathogenesis. Such dual approaches, which combine JAK2 inhibitors with Bcl-2/Bcl-xL inhibition, bromodomain inhibition, interferon-alpha, PI3K pathway, MAPK/ERK pathway inhibition, or others, are in clinical evaluation and highlight the significance as well as the promise of therapeutic developments in MPN  »

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[EPguy]

Good info. The background info has familiar things, but nicely laid out, see some here:

CALR has potential good future treatments since it's visible (this is discussed in other posts re immune therapy)

"Mutant CALR is secreted by the ER, associates with the thrombopoietin receptor, and can be detected at the cell surface, a finding that may prove useful for therapeutic approaches"

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Triple Neg has Jak2 like features and may be good for Jak-i therapies: “triple-negative” MPN patients who lack a driver mutation in JAK2, CALR, or MPL show activated JAK2 signaling, highlighting the significance of the JAK2 signaling network for MPN pathogenesis. This finding also provides a rational basis for JAK2 inhibitor treatment in triple-negative MPN patients"

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Inflammation: "A relationship between chronic inflammation and clonal development was corroborated by the finding that TNFα promotes clonal expansion of JAK2 V617F-mutated cells, while the absence of TNFα in JAK2 V617F-transduced bone marrow cells was able to abolish the MPN phenotype in murine models...The persistent inflammatory milieu in MPN has been shown to promote bone marrow fibrosis and constitutional symptoms, correlating with an unfavorable prognosis "

NAC supplement is known to help with TNFα and a phase 1/2 trial on NAC for MPN is ongoing. Their ref [42] here is by Dr. Fleischman, the NAC trial person.

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Status at Dx is prognostic: "Risk of leukemic transformation is associated with the overall number of acquired mutations, and the vast majority of these are already detectable at MPN diagnosis"

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While Rux is approved for PV, "In ET, ruxolitinib has not shown additional clinical value so far"

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Rux is not strong at disease modification: "Reductions in mutant allele burden are modest, and it has been demonstrated that clonal evolution is progressing during treatment with, e.g., ruxolitinib partial molecular remission, defined as a 50% reduction in JAK2 V617F allele burden in patients with at least 20% mutant allelic burden at baseline, is achieved in <10% of patients."

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We see members on Rux with Shingles, suggests be sure to get the shingles vax, with Dr approval, before starting Rux: "particularly reactivation of Herpes zoster, but also reactivation of tuberculosis, cryptococcal meningoencephalitis, Pneumocystis jirovecii pneumonia, hepatitis B, toxoplasmosis, or cytomegalovirus retinitis have been reported underscoring the importance of increased vigilance"

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Go after Jak2 when it's in a different state: "Type 2 JAK2 inhibition, which interferes with JAK2 in the inactive conformation, has shown promising effects on mutant allele burden in preclinical studies" Problem is all the refs I find here are ~2015, if there's nothing fresh it might not be working out.

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Section on combo therapies looks most promising, I feel the same applies to IFN, (IFN+ something) .

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CHIP is a sort of pre-MPN mutant state of usually elderly, and is more seen lately because allele tests are more sensitive: "CHIP Prevalence significantly depends on the applied method and its sensitivity to detect variant allele frequencies and may therefore be higher"