Description: A hit-to-lead to clinical trials project. Selvita has developed INH1972, a first in class, orally bioavailable small molecule dual kinase inhibitor
for the treatment of Acute Myeloid Leukaemia (AML). This project was initiated at an early hit stage and was progressed from that point through multiple stages
of optimization to the initiation of clinical trials (a Phase 1 trial was successfully completed in Q1 2020).

Actions: All of the chemistry and in vitro biology on this project was designed and executed within Selvita. From the initial start point, the development
of structure activity relationships and optimization of properties was strongly supported by our molecular modelling and with extensive crystallographic studies using in-house produced and crystallized target protein.

The optimisations leading to the selection of INH1972 as a preclinical development candidates involved iterative refinement of the inhibitor molecular structures in order to achieve a “good” profile of activity across the biology and ADME cascades, to deliver new intellectual property in filed patent appliications and to ensure that the advanced leads performed adequately in all pharmacokinetic and pharmacodynamic assessments.

INH1972 strongly binds to all three isoforms of TARGET1 and, very importantly, to several mutated versions of TARGET2 kinase.

Such “selective unselectivity” covering isoforms and mutants of both targets gives a hope for activity against broad range of genetic variations of the disease including also cases which are resistant to purely selective inhibitors.

It was shown that TARGET1 kinases govern TARGET2-mutant signaling and that their pharmacological or genetic inhibition restores cell sensitivity to TARGET2 inhibitors (Science Advances; 2015). Selvita also showed the same effect achieved by synergistic TARGET1 and TARGET2 inhibition by INH1972.

  • Mutations of TARGET2 kinase increase resistance against selective inhibitor REF2
  • Dual TARGET1/TARGET2 inhibitor, INH1972, remains similarly active regardless of the mutations resistant to REF2 treatment
  • REF1, a selective TARGET1 inhibitor, did not influence cell viability in applied concentration range

Key deliverables and challenges addressed:

  • Hit to lead series selected for lead optimization
  • Solubility optimized to make very simple formulation for oral administration possible
  • CYP inhibition managed
  • Synthesis optimized for easy scale up
  • Several hundred-gram batches were synthesized in house
  • Target protein produced and crystalized
  • Potential candidates evaluated