An Oncology biotech pioneering  RAD51 inhibition to treat high replication stress tumors

Pipeline

Satya’s Pipeline comprises First-In-Class and Best-In-Class
Targets focused on DDR pathway and Oncogenes.

TARGET

MOA / INDICATION

BIO MARKER

RIGHTS

EARLY DISCOVERY

LEAD OPTIMIZATION

PRE - CLINICAL

IND

RAD51:BRCA2 disruptor

DDR; PARPi-resistant Ovarian and Breast cancers

RAD51

Global

87%

SOS1

Oncogene; NSCLC, CRC

EGFR mutation & Pan RAS mutation

Global

76%

Undisclosed

DDR/ Cell cycle

Undisclosed

Partnered

Partnered with a Global Oncology Biotech

KIF18A

DDR; Solid tumors

CIN+ve cells

Global

49%

PARG
(covalent inhibitor)

DDR; Breast and Ovarian cancers

HRD

Global

35%

USP1

DDR; Breast and Ovarian cancers

HRD

Global

9%

Pipeline

Satya’s Pipeline comprises First-In-Class and Best-In-Class
Targets focused on DDR pathway and Oncogenes.

TARGET

MOA / INDICATION

BIO MARKER

RIGHTS

EARLY DISCOVERY

LEAD OPTIMIZATION

PRE - CLINICAL

IND

RAD51:BRCA2 disruptor

DDR; PARPi-resistant Ovarian and Breast cancers

RAD51

Global

91%

SOS1

Oncogene; NSCLC, CRC

EGFR mutation & Pan RAS mutation

Global

77%

Undisclosed

DDR/ Cell cycle

Undisclosed

Partnered

Partnered with a Global Oncology Biotech

KIF18A

DDR; Solid tumors

CIN+ve cells

Global

49%

PARG
(covalent inhibitor)

DDR; Breast and Ovarian cancers

HRD

Global

35%

USP1

DDR; Breast and Ovarian cancers

HRD

Global

11%

RAD51:BRCA2 disruptor

  • SAT-122 is a first-of-its-kind disruptor of RAD51:BRCA2 interaction, a novel mechanism in the DDR sapce
 
    • The centrality and functionality of RAD51 in the DDR pathway confers upon it a broad role in various replication stress-induced cancers. Thus, there is a potentially wide patient base that can be treated with this class of drugs.
    • Our candidate compound, by specifically targeting RAD51:BRCA2 inhibition: a) transiently prevents nuclear RAD51 foci formation; b) has no effect on RAD51 expression; c) does not affect any of the other functionalities of RAD51 (ATP hydrolysis, multimerization or DNA binding); and d) is unlikely to lead to overt toxicities
    • SAT-122 is preferentially active towards RAD51 high & BRCA2 WT tumors while sparing normal cells
    • SAT-122 is clinically being positioned for PARPi-resistant ovarian and breast cancer patients, a high clinically unmet need. These patients have high RAD51 foci both as a biomarker and driver of resistance.
    • SAT-122 is designed to offer a potentially significantly better safety window compared to other HR pathway inhibitors including CHK 1/2 and ATR inhibitors

Ref: Annals of Oncology 29: 1203–1210, 2018; Clinical Breast Cancer Volume 18, Issue 2, April 2018, Pages 184-188; Clin Cancer Res. 2017 November 01; 23(21):6708–6720 Cancer Cell International (2023) 23:231 BMB Rep. 2019; 52(2): 151-156] Plos one 17.8 (2022): e0266645. Cancers 13.12 (2021): 2930. Nature Communications 14.1 (2023): 7003.

SAT-122, the IND-candidate, has demonstrated excellent efficacy in multiple ovarian cancer xenograft models, as a single angle and in combination with chemo and PARP inhibitors while demonstrating an excellent safety profile

SOS1

    • SOS1 is a guanine nucleotide exchange factor for RAS proteins involved in activating Ras. Inhibition of SOS1 results in lowering the Ras-GTP activated state, inhibiting the RAS-MEK-ERK pathway and lowering proliferation, in both WT and the various mutant Ras isoforms
    • SOS1 inhibition is synthetic lethal with activating SHP2 mutations (10-20% of many of solid tumors). 
    • SOS1 acts as a potential driver in late stage Hepatocellular Carcinoma (HCC) & Receptor Tyrosine Kinase (RTK) resistant mutant EGFR bearing cancers

Satya’s SOS1 inhibitors demonstrate complete pERK and pAKT inhibition across various cell lines and best-in-class efficacy in a KRAS driven cancer xenograft model.

Ref: Adapted from Cancers 15.20 (2023): 5015

Parg

    • Despite the success of PARP inhibitors, drug resistance is a clinical hurdle. Loss of PAR glycohydrolase (PARG) is identified as a major resistance mechanism. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Thus, PARG ihhibition provides an therapeutic opportunity to sensitize PARP inhibitors further.
    • Additionally, PARG inhibition disrupts DNA damage repair cycle and leads to cell death. PARG depleted/ inhibited cells show increased sensitivity to DNA damage agents.
    • Covalent inhibition offers a significantly higher and more sustained PD resulting in a best-in-class pharmacological profile 
 

We anticipate identification of a differentiated candidate compound by end-2024

Eva Gogola et al, Cancer Cell June 2019

KIF18A

  • Chromosomal instability (CIN), characterized by frequent mis-segregation of chromosomes during mitosis, is a hallmark of tumor cells caused by changes in the dynamics and control of microtubules that comprise the mitotic spindle. Thus, CIN +ve tumor cells may respond differently than normal diploid cells to treatments that target mitotic spindle regulation. KIF18A is required for proliferation of CIN +ve cells derived from triple negative breast cancer or colorectal cancer tumors but not in near-diploid cells. CIN +ve tumor cells exhibit mitotic delays, and increased cell death following inhibition of KIF18A. Sensitivity to KIF18A knockdown is strongly correlated with centrosome fragmentation. (Carolyn Marquis et al., Nature Communications, 2021).

Satya's KIF18A inhibitor is a highly differentiated best-in-class compound characterized by superior pharmacokinetic properties (clearance in 12 hrs compared to 48 hrs in competitor compounds) potentially leading to superior safety and druggability

Louise Jannsen et al., Current Biology September 2018

USP1

  • USP1 represents a promising target for drug intervention because of its involvement in Translesion synthesis (TLS) and intra-strand crosslink repair important for normal DNA damage response
  • The FA(Fanconi anemia) pathway regulates the repair of DNA crosslinks, a critical step in this pathway is the monoubiquitination and deubiquitination of FANCD2
  • PCNA ubiquitination is central to the normal DNA damage response process in eukaryotes. Its deubiquitimation is important for translesion DNA synthesis.
  • USP1 has been shown to deubiquitinate PCNA and FANCD2 in cells. Inhibition of USP1 causes ubiquitination of PCNA & FANCD2 leading to accummulation of damaged DNA leading to cell death

García-Santisteban, Iraia, et al., Molecular cancer 12.1 (2013): 1-12.

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