Development of highly selective, potent, orally available PIM1 inhibitor BLX-0631 shows a therapeutics potential in Systemic Lupus Erythematosus (SLE) models

---

Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B900
Abstract ID: 6301

Presenting Author:
Hariprasad Vankayalapati , Chief Scientific Officer at Biolexis Therapeut.

Abstract:

Background: PIM1, PIM2, and PIM3 are constitutively active and play a vital role in cell proliferation, differentiation, and survival. PIM1 kinase is involved in cell cycle progression and apoptosis in cancers well explored. Due to its role in immune cell development, and autoimmune function to SLE, PIM1 is a therapeutic target of interest, we investigated with our lead BLX-0631.

Methods: SLE patients, healthy donor PMBC samples by Kinase-Glo, CellTiter-Glo, and qPCR and in vitro ADME-Tox, safety, metabolic, efflux, clearance, stability, PK, and SLE NZBWF1/J mouse model experiments were conducted.

Results: MolecuLern fragment library, PIM1 crystal structure, scaffold hopping, and 3-point pharmacophores provided a synthesizable library. 5 fragments that inhibit the PIM1 with an IC₅₀ of 17-344 nM served as leads for the optimization, synthesis, and testing of 40 PIM1i. Lead BLX-0631 exhibited IC_50s of 15, 121, and 47 nM potency against PIM1, PIM2, and PIM3 and was selective in 468 kinome panels. BLX-0631 decreased IL-1b, and TNF-α levels to >80%. Consistent with SLE ex-vivo results, BLX-0631 at 10 and 30 mg/kg p.o demonstrated significant efficacy in reducing plasma creatinine, blood urea nitrogen, and histopathology scores when compared with vehicle. PK properties, safety, and efficacy results of BLX-0631 will be presented. 

Conclusions: Ex vivo SLE patient samples and NZBWF1/J mouse model data support our selection of BLX-0631 as a candidate for IND-enabling studies.